U.S. patent number 7,375,087 [Application Number 10/523,820] was granted by the patent office on 2008-05-20 for pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof.
This patent grant is currently assigned to Kissei Pharmaceutical Co., Ltd.. Invention is credited to Nobuhiko Fushimi, Masayuki Isaji, Toshihide Shibazaki, Kazuo Shimizu, Hirotaka Teranishi, Shigeru Yonekubo.
United States Patent |
7,375,087 |
Teranishi , et al. |
May 20, 2008 |
Pyrazole derivative, medicinal composition containing the same,
medicinal use thereof, and intermediate for production thereof
Abstract
The present invention provides pyrazole derivatives represented
by the general formula: ##STR00001## wherein R.sup.1 represents H,
an optionally substituted C.sub.1-6 alkyl group etc.; one of Q and
T represents a group represented by the general formula:
##STR00002## or a group represented by the general formula:
##STR00003## while the other represents an optionally substituted
C.sub.1-6 alkyl group etc.; R.sup.2 represents H, a halogen atom,
OH, an optionally substituted C.sub.1-6 alkyl group etc.; X
represents a single bond, O or S; Y represents a single bond, a
C.sub.1-6 alkylene group etc.; Z represents CO or SO.sub.2; R.sup.4
and R.sup.5 represent H, an optionally substituted C.sub.1-6 alkyl
group etc.; and R.sup.3, R.sup.6 and R.sup.7 represent H, a halogen
atom etc., pharmaceutically acceptable salts thereof or prodrugs
thereof, which exhibit an excellent inhibitory activity in human
SGLT1 and are useful as agents for the prevention or treatment of a
disease associated with hyperglycemia such as diabetes, diabetic
complications or obesity, and pharmaceutical compositions
comprising the same, pharmaceutical uses thereof, and intermediates
for production thereof.
Inventors: |
Teranishi; Hirotaka
(Hotaka-machi, JP), Fushimi; Nobuhiko (Hotaka-machi,
JP), Yonekubo; Shigeru (Hotaka-machi, JP),
Shimizu; Kazuo (Hotaka-machi, JP), Shibazaki;
Toshihide (Hotaka-machi, JP), Isaji; Masayuki
(Hotaka-machi, JP) |
Assignee: |
Kissei Pharmaceutical Co., Ltd.
(Nagano, JP)
|
Family
ID: |
31719857 |
Appl.
No.: |
10/523,820 |
Filed: |
August 7, 2003 |
PCT
Filed: |
August 07, 2003 |
PCT No.: |
PCT/JP03/10048 |
371(c)(1),(2),(4) Date: |
February 04, 2005 |
PCT
Pub. No.: |
WO2004/014932 |
PCT
Pub. Date: |
February 19, 2004 |
Prior Publication Data
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|
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Document
Identifier |
Publication Date |
|
US 20060166899 A1 |
Jul 27, 2006 |
|
Foreign Application Priority Data
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|
|
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Aug 8, 2002 [JP] |
|
|
2002-232074 |
Nov 5, 2002 [JP] |
|
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2002-321729 |
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Current U.S.
Class: |
514/25; 536/17.2;
536/18.1; 536/17.3; 514/27 |
Current CPC
Class: |
A61P
19/06 (20180101); A61P 25/00 (20180101); A61P
3/06 (20180101); A61P 9/12 (20180101); A61P
3/04 (20180101); C07H 17/02 (20130101); A61P
13/02 (20180101); A61P 9/10 (20180101); A61P
9/04 (20180101); A61P 43/00 (20180101); A61P
3/00 (20180101); A61P 3/10 (20180101) |
Current International
Class: |
A01N
43/04 (20060101); A61K 31/70 (20060101); C07H
15/00 (20060101) |
Field of
Search: |
;536/17.2,17.3,18.1
;514/25,27 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Goodman & Gilman's: The Pharmacological Basis of Therapeutics,
10th Edition, McGraw-Hill Medical Publishing Division, 2001, pp.
54-56. cited by examiner.
|
Primary Examiner: Jiang; Shaojia Anna
Assistant Examiner: McIntosh, III; Traviss C.
Attorney, Agent or Firm: Sughrue Mion, PLLC
Claims
The invention claimed is:
1. A pyrazole derivative represented by the general formula:
##STR00027## wherein R.sup.1 represents a hydrogen atom, a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
hydroxy(C.sub.2-6 alkyl) group, a C.sub.3-7 cycloalkyl group, a
C.sub.3-7 cycloalkyl-substituted (C.sub.1-6 alkyl) group, an aryl
group which may have the same or different 1 to 3 substituents
selected from the group consisting of a halogen atom, a hydroxy
group, an amino group, a C.sub.1-6 alkyl group and a C.sub.1-6
alkoxy group, or an aryl(C.sub.1-6 alkyl) group which may have the
same or different 1 to 3 substituents selected from the group
consisting of a halogen atom, a hydroxy group, an amino group, a
C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group on the ring; one
of Q and T represents a group represented by the formula:
##STR00028## or a group represented by the formula: ##STR00029##
while the other represents a C.sub.1-6 alkyl group, a
halo(C.sub.1-6 alkyl) group, a C.sub.1-6 alkoxy-substituted
(C.sub.1-6 alkyl) group or a C.sub.3-7 cycloalkyl group; R.sup.2
represents a hydrogen atom, a halogen atom, a hydroxy group, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a halo(C.sub.1-6 alkyl) group, a halo(C.sub.1-6
alkoxy) group, a C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkoxy)
group, a C.sub.3-7 cycloalkyl-substituted (C.sub.2-6 alkoxy) group
or a group of the general formula: -A-R.sup.8 in which A represents
a single bond, an oxygen atom, a methylene group, an ethylene
group, --OCH.sub.2-- or --CH.sub.2O--; and R.sup.8 represents a
C.sub.3-7 cycloalkyl group, a C.sub.2-6 heterocycloalkyl group, an
aryl group which may have the same or different 1 to 3 substituents
selected from the group consisting of a halogen atom, a hydroxy
group, an amino group, a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy
group, a C.sub.2-6 alkenyloxy group, a halo(C.sub.1-6 alkyl) group,
a hydroxy(C.sub.1-6 alkyl) group, a carboxy group, a C.sub.2-7
alkoxycarbonyl group, a cyano group and a nitro group, or a
heteroaryl group which may have a substituent selected from the
group consisting of a halogen atom and a C.sub.1-6 alkyl group; X
represents a single bond, an oxygen atom or a sulfur atom; Y
represents a single bond, a C.sub.1-6 alkylene group or a C.sub.2-6
alkenylene group with the proviso that X is a single bond when Y is
a single bond; Z represents a carbonyl group or a sulfonyl group;
R.sup.4 and R.sup.5 are the same or different and each represents a
hydrogen atom or a C.sub.1-6 alkyl group which may have the same or
different 1 to 3 groups selected from the following substituent
group (i), or they bind together with the neighboring nitrogen atom
to form a C.sub.2-6 cyclic amino group which may have a substituent
selected from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group; R.sup.3, R.sup.6 and R.sup.7 are
the same or different, and each represents a hydrogen atom, a
halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-6 alkoxy group;
and substituent group (i) consists of a hydroxy group, an amino
group, a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a
sulfamide group, a mono or di(C.sub.1-6 alkyl)ureido group, a mono
or di(C.sub.1-6 alkyl)sulfamide group, a C.sub.2-7 acylamino group,
a C.sub.1-6 alkylsulfonylamino group, a group of the general
formula: --CON(R.sup.9)R.sup.10 which R.sup.9 and R.sup.10 are the
same or different, and each represents a hydrogen atom or a
C.sub.1-6 alkyl group which may have the same or different 1 to 3
substituents selected from the group consisting of a hydroxy group,
an amino group, a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a mono or
di(C.sub.1-6 alkyl)ureido group, a C.sub.2-7 acylamino group, a
C.sub.1-6 alkylsulfonylamino group and a carbamoyl group, or they
bind together with the neighboring nitrogen atom to form a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, a C.sub.3-7 cycloalkyl group, a
C.sub.2-6 heterocycloalkyl group, an aryl group which may have the
same or different 1 to 3 substituents selected from the group
consisting of a halogen atom, a hydroxy group, an amino group, a
C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group, a heteroaryl
group which may have a substituent selected from the group
consisting of a halogen atom and a C.sub.1-6 alkyl group, a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, and a C.sub.1-4 aromatic cyclic
amino group which may have a C.sub.1-6 alkyl group as a
substituent, or a pharmaceutically acceptable salt thereof.
2. A pyrazole derivative as claimed in claim 1, wherein Y
represents a C.sub.1-6 alkylene group or a C.sub.2-6 alkenylene
group; one of R.sup.4 and R.sup.5 represents a C.sub.1-6 alkyl
group which has the same or different 1 to 3 groups selected from
the following substituent group (i), the other represents a
hydrogen atom or a C.sub.1-6 alkyl group which may have the same or
different 1 to 3 groups selected from the following substituent
group (i); and substituent group (i) consists of a hydroxy group,
an amino group, a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a
sulfamide group, a mono or di(C.sub.1-6 alkyl)ureido group, a mono
or di(C.sub.1-6 alkyl)sulfamide group, a C.sub.2-7 acylamino group,
a C.sub.1-6 alkylsulfonylamino group, a group of the general
formula; --CON(R.sup.9)R.sup.10 in which R.sup.9 and R.sup.10 are
the same or different, and each represents a hydrogen atom or a
C.sub.1-6 alkyl group which may have the same or different 1 to 3
substituents selected from the group consisting of a hydroxy group,
an amino group, a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a mono or
di(C.sub.1-6 alkyl)ureido group, a C.sub.2-7 acylamino group, a
C.sub.1-6 alkylsulfonylamino group and a carbamoyl group, or they
bind together with the neighboring nitrogen atom to form a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, a C.sub.3-7 cycloalkyl group, a
C.sub.2-6 heterocycloalkyl group, an aryl group which may have the
same or different 1 to 3 substituents selected from the group
consisting of a halogen atom, a hydroxy group, an amino group, a
C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group, a heteroaryl
group which may have a substituent selected from the group
consisting of a halogen atom and a C.sub.1-6 alkyl group, a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, and a C.sub.1-4 aromatic cyclic
amino group which may have a C.sub.1-6 alkyl group as a
substituent, or a pharmaceutically acceptable salt thereof.
3. A pyrazole derivative as claimed in claim 2, wherein one of
R.sup.4 and R.sup.5 represents a C.sub.1-6 alkyl group which has a
group selected from the following substituent group (iA), the other
represents a hydrogen atom; and substituent group (iA) is a group
of the general formula: --CON(R.sup.9A)R.sup.10A in which R.sup.9A
and R.sup.10A bind tog with the neighboring nitrogen atom to form a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, or a pharmaceutically acceptable
salt thereof.
4. A pyrazole derivative as claimed in claim 1, wherein X
represents a single bond; and Y represents a trimethylene group or
a 1-propenylene group, or a pharmaceutically acceptable salt
thereof.
5. A pyrazole derivative as claimed in claim 1, wherein X
represents an oxygen atom; and Y represents an ethylene group or a
trimethylene group, or a pharmaceutically acceptable salt
thereof.
6. A pyrazole derivative as claimed in claim 1, wherein X
represents a single bond; Y represents a single bond; one of
R.sup.4 and R.sup.5 represents a C.sub.1-6 alkyl group which has
the same or different 1 to 3 groups selected from the following
substituent group (iB), the other represents a hydrogen atom or a
C.sub.1-6 alkyl group which may have the same or different 1 to 3
groups selected from the following substituent group (iB); and
substituent group (iB) consists of an ureido group, a sulfamide
group, a mono or di(C.sub.1-6 alkyl)ureido group, a mono or
di(C.sub.1-6 alkyl)sulfamide group, a C.sub.1-6 alkylsulfonylamino
group, a group of the general formula: --CON(R.sup.9B)R.sup.10B in
which one of R.sup.9A and R.sup.10B represents a C.sub.1-6 alkyl
group which has the same or different 1 to 3 substituents selected
from the group consisting of a hydroxy group, an amino group, a
mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureldo group, a mono or
di(C.sub.1-6 alkyl)ureido group, a C.sub.2-7 acylamino group, a
C.sub.1-6 alkylsulfonylamino group and a carbamoyl group, the other
represents a hydrogen atom, a C.sub.1-6 alkyl group which may have
the same or different 1 to 3 substituents selected from the group
consisting of a hydroxy group, an amino group, a mono or
di(C.sub.1-6 alkyl)amino group, a mono or di[hydroxy(C.sub.1-6
alkyl)]amino group, an ureido group, a mono or di(C.sub.1-6
alkyl)ureido group, a C.sub.2-7 acylamino group, a C.sub.1-6
alkylsulfonylamino group and a carbamoyl group, or they bind
together with the neighboring nitrogen atom to form a C.sub.2-6
cyclic amino group which may have a substituent selected from the
group consisting of a C.sub.1-6 alkyl group and a hydroxy(C.sub.1-6
alkyl) group, a C.sub.3-7 cycloalkyl group, a C.sub.2-6
heterocycloalkyl group, an aryl group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group, an amino group, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group, a heteroaryl group which may
have a substituent selected from the group consisting of a halogen
atom and a C.sub.1-6 alkyl group, a C.sub.2-6 cyclic amino group
which may have a substituent selected from the group consisting of
a C.sub.1-6 alkyl group and a hydroxy(C.sub.1-6 alkyl) group, and a
C.sub.1-4 aromatic cyclic amino group which may have a C.sub.1-6
alkyl group as a substituent, or a pharmaceutically acceptable salt
thereof.
7. A pyrazole derivative as claimed in claim 1, wherein R.sup.1
represents a hydrogen atom or a hydroxy(C.sub.2-6 alkyl) group; T
represents a group represented by the formula: ##STR00030## or a
group represented by the formula: ##STR00031## wherein Q represents
a C.sub.1-6 alkyl group or a halo(C.sub.1-6 alkyl) group; and
R.sup.3, R.sup.6 and R.sup.7 represent a hydrogen atom, or a
pharmaceutically acceptable salt thereof.
8. A pyrazole derivative as claimed in claim 1, wherein one of Q
and T represents a group represented by the formula: ##STR00032##
and the other represents a C.sub.1-6 alkyl group, a halo(C.sub.1-6
alkyl) group, a C.sub.1-6 alkoxy-substituted C.sub.1-6 alkyl) group
or a C.sub.3-7 cycloalkyl group, or a pharmaceutically acceptable
salt thereof.
9. A pyrazole derivative as claimed in claim 7, wherein T
represents a group represented by the formula: ##STR00033## or a
pharmaceutically acceptable salt thereof.
10. A pyrazole derivative as claimed in claim 7, wherein Q
represents an isopropyl group, or a pharmaceutically acceptable
salt thereof.
11. A prodrug of a pyrazole derivative as claimed in claim 1 or a
pharmaceutically acceptable salt thereof.
12. A prodrug as claimed in claim 11, wherein T represents a group
represented by the formula: ##STR00034## or a group represented by
the formula: ##STR00035## in which the hydroxy group at the
4-position is substituted by a glucopyranosyl group or a
galactopyranosyl group, or the hydroxy group at the 6-position is
substituted by a glucopyranosyl group, a galactopyranosyl group, a
C.sub.2-7 acyl group, a C.sub.1-6 alkoxy-substituted (C.sub.2-7
acyl) group, a C.sub.2-7 alkoxycarbonyl-substituted (C.sub.2-7
acyl) group, a C.sub.2-7 alkoxycarbonyl group, an aryl(C.sub.2-7
alkoxycarbonyl) group or a C.sub.1-6 alkoxy-substituted (C.sub.2-7
alkoxycarbonyl) group.
13. A pyrazole derivative as claimed in claim 1, which is a
compound selected from the following group:
4-[(4-{3-[1-carbamoyl-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)me-
thyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperaz-
in-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopro-
pyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[2-(dimethylamin-
o)ethylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyraz-
ole;
4-[(4-{3-[1-(2-aminoethylcarbamoyl)-1-(methyl)-ethylcarbamoyl]propyl}-
phenyl)methyl]-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpipera-
zin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyra-
zole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-isoprop-
ylpiperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)-ethylca-
rbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{(1E)-3-[(S)-2-hydroxy-1-(methyl)-et-
hylcarbamoyl]prop-1-enyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}--
1H-pyrazole;
3-(.beta.3-D-glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)-ethyl-
carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)c-
arbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-1H-pyraz-
ole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1--
yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)-2-methylphenyl]methyl}-1H-p-
yrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]--
5-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-1-(3-hydroxypropyl)-5-isopropyl-4-{[4-(3-
-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]met-
hyl}-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-1H-py-
razole;
4-{[2-fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylca-
rbamoyl}propyl)phenyl]methyl}-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-
-1H-pyrazole;
4-{[2-chloro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl-
}propyl)phenyl]methyl}-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyraz-
ole, and pharmaceutically acceptable salts thereof.
14. A pyrazole derivative as claimed in claim 13, which is a
compound selected from the following group:
3-(.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperaz-
in-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopro-
pyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpipera-
zin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyra-
zole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpip-
erazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]met-
hyl}-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)c-
arbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-1H-pyraz-
ole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1--
yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)-2-methylphenyl]methyl}-1H-p-
yrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-1H-py-
razole;
4-{[2-fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylca-
rbamoyl}propyl)phenyl]methyl}-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-
-1H-pyrazole, and pharmaceutically acceptable salts thereof.
15. A pharmaceutical composition comprising as an active ingredient
a pyrazole derivative as claimed in claim 1, a pharmaceutically
acceptable salt thereof or a prodrug thereof.
16. A pharmaceutical composition as claimed in claim 15, wherein
the dosage form is sustained release formulation.
17. A method for the treatment of a disease associated with
hyperglycemia, which comprises administering an effective amount of
a pyrazole derivative as claimed in claim 1, a pharmaceutically
acceptable salt thereof or a prodrug thereof to a subject in need
thereof.
18. A method for the inhibition of advancing impaired glucose
tolerance into diabetes in a subject, which comprises administering
an effective amount of a pyrazole derivative as claimed in claim 1,
a pharmaceutically acceptable salt thereof or a prodrug thereof to
a subject in need thereof.
19. A pyrazole derivative represented by the general formula:
##STR00036## wherein R.sup.11 represents a hydrogen atom, a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
hydroxy(C.sub.2-6 alkyl) group which may have a protective group, a
C.sub.3-7 cycloalkyl group, a C.sub.3-7 cycloalkyl-substituted
(C.sub.1-6 alkyl) group, an aryl group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group which may have a protective group,
an amino group which may have a protective group, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group, or an aryl(C.sub.1-6 alkyl)
group which may have the same or different 1 to 3 substituents
selected from the group consisting of a halogen atom, a hydroxy
group which may have a protective group, an amino group which may
have a protective group, a C.sub.1-6 alkyl group and a C.sub.1-6
alkoxy group on the ring; one of Q.sup.2 and T.sup.2 represents a
2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy group or a
2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy group, while
the other represents a C.sub.1-6 alkyl group, a halo(C.sub.1-6
alkyl) group, a C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkyl)
group or a C.sub.3-7 cycloalkyl group; R.sup.12 represents a
hydrogen atom, a halogen atom, a hydroxy group which may have a
protective group, a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy
group, a C.sub.1-6 alkylthio group, a halo(C.sub.1-6 alkyl) group,
a halo(C.sub.1-6 alkoxy) group, a C.sub.1-6 alkoxy-substituted
(C.sub.1-6 alkoxy) group, a C.sub.3-7 cycloalkyl-substituted
(C.sub.2-6 alkoxy) group or a group of the general formula:
-A-R.sup.18 in which A represents a single bond, an oxygen atom, a
methylene group, an ethylene group, --OCH.sub.2-- or --CH.sub.2O--;
and R.sup.18 represents a C.sub.3-7 cycloalkyl group, a C.sub.2-6
heterocycloalkyl group, an aryl group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group which may have a protective group,
an amino group which may have a protective group, a C.sub.1-6 alkyl
group, a C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy group, a
halo(C.sub.1-6 alkyl) group, a hydroxy(C.sub.1-6 alkyl) group which
may have a protective group, a carboxy group which may have a
protective group, a C.sub.2-7 alkoxycarbonyl group, a cyano group
and a nitro group, or a heteroaryl group which may have a
substituent selected from the group consisting of a halogen atom
and a C.sub.1-6 alkyl group; X represents a single bond, an oxygen
atom or a sulfur atom; Y represents a single bond, a C.sub.1-6
alkylene group or a C.sub.2-6 alkenylene group with the proviso
that X is a single bond when Y is a single bond; Z represents a
carbonyl group or a sulfonyl group; R.sup.14 and R.sup.15 are the
same or different, and each represents a hydrogen atom or a
C.sub.1-6 alkyl group which may have the same or different 1 to 3
groups selected from the following substituent group (ii), or they
bind together with the neighboring nitrogen atom to form a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group which may have a protective group;
R.sup.3, R.sup.6 and R.sup.7 are the same or different, and each
represents a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group
or a C.sub.1-6 alkoxy group; and substituent group (ii) consists of
a hydroxy group which may have a protective group, an amino group
which may have a protective group, a mono or di(C.sub.1-6
alkyl)amino group which may have a protective group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group which may have a protective
group, an ureido group, a sulfamide group, a mono or di(C.sub.1-6
alkyl)ureido group, a mono or di(C.sub.1-6 alkyl)sulfamide group, a
C.sub.2-7 acylamino group, a C.sub.1-6 alkylsulfonylamino group, a
group of the general formula: --CON(R.sup.19)R.sup.20 in which
R.sup.19 and R.sup.20 are the same or different, and each
represents a hydrogen atom or a C.sub.1-6 alkyl group which may
have the same or different 1 to 3 substituents selected from the
group consisting of a hydroxy group which may have a protective
group, an amino group which may have a protective group, a mono or
di(C.sub.1-6 alkyl)amino group which may have a protective group, a
mono or di[hydroxy(C.sub.1-6 alkyl)]amino group which may have a
protective group, an ureido group, a mono or di(C.sub.1-6
alkyl)ureido group, a C.sub.2-7 acylamino group, a C.sub.1-6
alkylsulfonylamino group and a carbamoyl group, or they bind
together with the neighboring nitrogen atom to form a C.sub.2-6
cyclic amino group which may have a substituent selected from the
group consisting of a C.sub.1-6 alkyl group and a hydroxy(C.sub.1-6
alkyl) group which may have a protective group, a C.sub.3-7
cycloalkyl group, a C.sub.2-6 heterocycloalkyl group, an aryl group
which may have the same or different 1 to 3 substituents selected
from the group consisting of a halogen atom, a hydroxy group which
may have a protective group, an amino group which may have a
protective group, a C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy
group, a heteroaryl group which may have a substituent selected
from the group consisting of a halogen atom and a C.sub.1-6 alkyl
group, a C.sub.2-6 cyclic amino group which may have a substituent
selected from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group which may have a protective group,
and a C.sub.1-4 aromatic cyclic amino group which may have a
C.sub.1-6 alkyl group as a substituent, or a salt thereof.
20. A pyrazole derivative as claimed in claim 2, wherein X
represents a single bond; and Y represents a trimethylene group or
a 1-propenylene group, or a pharmaceutically acceptable salt
thereof.
21. A pyrazole derivative as claimed in claim 3, wherein X
represents a single bond; and Y represents a trimethylene group or
a 1-propenylene group, or a pharmaceutically acceptable salt
thereof.
22. A pyrazole derivative as claimed in claim 2, wherein X
represents an oxygen atom; and Y represents an ethylene group or a
trimethylene group, or a pharmaceutically acceptable salt
thereof.
23. A pyrazole derivative as claimed in claim 3, wherein X
represents an oxygen atom; and Y represents an ethylene group or a
trimethylene group, or a pharmaceutically acceptable salt
thereof.
24. A pyrazole derivative as claimed in claim 2, wherein R.sup.1
represents a hydrogen atom or a hydroxy(C.sub.2-6 alkyl) group; T
represents a group represented by the formula: ##STR00037## or a
group represented by the formula: ##STR00038## wherein Q represents
a C.sub.1-6 alkyl group or a halo(C.sub.1-6 alkyl) group; and
R.sup.3, R.sup.6 and R.sup.7 represent a hydrogen atom, or a
pharmaceutically acceptable salt thereof.
25. A pyrazole derivative as claimed in claim 3, wherein R.sup.1
represents a hydrogen atom or a hydroxy(C.sub.2-6 alkyl) group; T
represents a group represented by the formula: ##STR00039## or a
group represented by the formula: ##STR00040## wherein Q represents
a C.sub.1-6 alkyl group or a halo(C.sub.1-6 alkyl) group; and
R.sup.3, R.sup.6 and R.sup.7 represent a hydrogen atom, or a
pharmaceutically acceptable salt thereof.
26. A pyrazole derivative as claimed in claim 2, wherein one of Q
and T represents a group represented by the formula: ##STR00041##
and the other represents a C.sub.1-6 alkyl group, a halo(C.sub.1-6
alkyl) group, a C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkyl)
group or a C.sub.3-7 cycloalkyl group, or a pharmaceutically
acceptable salt thereof.
27. A pyrazole derivative as claimed in claim 3, wherein one of Q
and T represents a group represented by the formula: ##STR00042##
and the other represents a C.sub.1-6 alkyl group, a halo(C.sub.1-6
alkyl) group, a C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkyl)
group or a C.sub.3-7 cycloalkyl group, or a pharmaceutically
acceptable salt thereof.
28. A pyrazole derivative as claimed in claim 8, wherein T
represents a group represented by the formula: ##STR00043## or a
pharmaceutically acceptable salt thereof.
29. A pyrazole derivative as claimed in claim 9, wherein Q
represents an isopropyl group, or a pharmaceutically acceptable
salt thereof.
Description
TECHNICAL FIELD
The present invention relates to pyrazole derivatives,
pharmaceutically acceptable salts thereof or prodrugs thereof which
are useful as medicaments, pharmaceutical compositions comprising
the same, pharmaceutical uses thereof and intermediates for
production thereof.
More particularly, the present invention relates to pyrazole
derivatives having an inhibitory activity inhuman SGLT1,
pharmaceutically acceptable salts thereof or prodrugs thereof which
are useful as agents for the prevention or treatment of a disease
associated with hyperglycemia such as diabetes, impaired glucose
tolerance, impaired fasting glycemia, diabetic complications or
obesity, pharmaceutical compositions comprising the same,
pharmaceutical uses thereof and intermediates for production
thereof.
BACKGROUND ART
Diabetes is one of lifestyle-related diseases with the background
of change of eating habit and lack of exercise. Hence, diet and
exercise therapies are performed in patients with diabetes.
Furthermore, when its sufficient control and continuous performance
are difficult, drug treatment is simultaneously performed. In
addition, it has been confirmed by large-scale clinical trial that
it is necessary to practice a long-term control of blood sugar
level strictly so as to prevent patients with diabetes from
occuring and advancing diabetic complications by receiving
treatment (see the following References 1 and 2). Furthermore, many
epidemiologic studies on impaired glucose tolerance and
macroangiopathy show that impaired glucose tolerance as the
boundary type is also a risk factor in macroangiopathy as well as
diabetes. Thus, needs to improve postprandial hyperglycemia have
been focused (see the following Reference 3).
In recent years, development of various antidiabetic agents has
been progressing with the background of a rapid increase of
patients with diabetes. For example, a-glucosidase inhibitors,
which delay carbohydrate digestion and absorption at the small
intestine, are used to improve postprandial hyperglycemia. It has
been also reported that a carbose, one of a-glucosidase inhibitors,
has an effect of preventing or delaying the incidence of diabetes
by applying to patients with impaired glucose tolerance (see the
following Reference 4). However, since a-glucosidase inhibitors do
not affect elevated glucose levels by ingesting a monosaccharide of
glucose (see the following Reference 5), with recently changing
compositions of sugars in meals, it has been desired to develop
agents which exert a wider range of activities inhibiting
carbohydrate absorption.
In the meantime, it has been known that SGLT1, sodium-dependent
glucose transporter 1, exists in the small intestine which controls
carbohydrate absorption. It has been also reported that
insufficiency of glucose and galactose absorption arises in
patients with dysfunction due to congenital abnormalities of human
SGLT1 (seethe following References 6-8). In addition, it has been
confirmed that SGLT1 is involved in glucose and galactose
absorption (see the following References 9 and 10).
Furthermore, it is confirmed that mRNA and protein of SGLT1
increase and absorption of glucoses are accelerated in OLETF rats
and rats with streptozotocin-induced diabetic symptoms (see the
following References 11 and 12). Generally in patients with
diabetes, carbohydrate digestion and absorption are increased. For
example, it is confirmed that mRNA and protein of SGLT1 are highly
increased in the human small intestine (see the following Reference
13).
Therefore, blocking a human SGLT1 activity inhibits absorption of
carbohydrates such as glucose at the small intestine, subsequently
can prevent increase of blood sugar level. Especially, it is
considered that delaying glucose absorption based on the above
mentioned mechanism is effective to normalize postprandial
hyperglycemia. In addition, since increase of SGLT1 in the small
intestine is thought to contribute to increased carbohydrate
absorption, fast development of agents, which have a potent
inhibitory activity in human SGLT1, has been desired for the
prevention or treatment of diabetes. Reference 1: The Diabetes
Control and Complications Trial Research Group, N. Engl. J. Med.,
1993.9, Vol. 329, No. 14, pp. 977-986; Reference 2: UK Prospective
Diabetes Study Group, Lancet, 1998.9, Vol. 352, No. 9131, pp.
837-853; Reference 3: Makoto, TOMINAGA, Endocrinology &
Diabetology, 2001.11, Vol. 13, No. 5, pp. 534-542; Reference 4:
Jean-Louis Chiasson and 5 persons, Lancet, 2002.6, Vol. 359, No.
9323, pp. 2072-2077; Reference 5: Hiroyuki, ODAKA and 3 persons,
Journal of Japanese Society of Nutrition and Food Science, 1992,
Vol. 45, No. 1, pp. 27-31; Reference 6: Tadao, BABA and 1 person,
Supplementary volume of Nippon Rinsho, Ryoikibetsu Shokogun, 1998,
No. 19, pp. 552-554; Reference 7: Michihiro, KASAHARA and 2
persons, Saishin Igaku, 1996.1, Vol. 51, No. 1, pp. 84-90;
Reference 8: Tomofusa, TSUCHIYA and 1 person, Nippon Rinsho,
1997.8, Vol. 55, No. 8, pp. 2131-2139; Reference 9: Yoshikatsu,
KANAI, Kidney and Dialysis, 1998.12, Vol. 45, extra edition, pp.
232-237; Reference 10: E. Turk and 4 persons, Nature, 1991.3, Vol.
350, pp. 354-356; Reference 11: Y. Fujita and 5 persons,
Diabetologia, 1998, Vol. 41, pp. 1459-1466; Reference 12: J. Dyer
and 5 persons, Biochemical Society Transactions, 1997, Vol. 25, p.
479S; Reference 13: J. Dyer and 4 persons, American Journal of
Physiology, 2002.2, Vol. 282, No. 2, pp. G241-G248
DISCLOSURE OF THE INVENTION
The present inventors have studied earnestly to find compounds
having an inhibitory activity in human SGLT1. As a result, it was
found that certain pyrazole derivatives represented by the
following general formula (I) show an inhibitory activity in human
SGLT1 at the small intestine and exert an excellent inhibitory
activity in increase of blood glucose level as shown below, thereby
forming the basis of the present invention.
The present invention is to provide novel pyrazole derivatives
which exert an excellent inhibitory activity of blood glucose level
increase by showing an inhibitory activity in human SGLT1 and
inhibiting absorption of carbohydrate such as glucose at the small
intestine, pharmaceutically acceptable salts thereof or prodrugs
thereof, and to provide pharmaceutical compositions comprising the
same, pharmaceutical uses thereof and intermediates for production
thereof.
This is, the present invention relates to
[1] a pyrazole derivative represented by the general formula:
##STR00004## wherein
R.sup.1 represents a hydrogen atom, a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a hydroxy(C.sub.2-6 alkyl) group, a
C.sub.3-7 cycloalkyl group, a C.sub.3-7 cycloalkyl-substituted
(C.sub.1-6 alkyl) group, an aryl group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group, an amino group, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group, or an aryl(C.sub.1-6 alkyl)
group which may have the same or different 1 to 3 substituents
selected from the group consisting of a halogen atom, a hydroxy
group, an amino group, a C.sub.1-6 alkyl group and a C.sub.1-6
alkoxy group on the ring;
one of Q and T represents a group represented by the formula:
##STR00005## or a group represented by the formula:
##STR00006##
while the other represents a C.sub.1-6 alkyl group, a
halo(C.sub.1-6 alkyl) group, a C.sub.1-6 alkoxy-substituted
(C.sub.1-6 alkyl) group or a C.sub.3-7 cycloalkyl group;
R.sup.2 represents a hydrogen atom, a halogen atom, a hydroxy
group, a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a
C.sub.1-6 alkylthio group, a halo(C.sub.1-6 alkyl) group, a
halo(C.sub.1-6 alkoxy) group, a C.sub.1-6 alkoxy-substituted
(C.sub.1-6 alkoxy) group, a C.sub.3-7 cycloalkyl-substituted
(C.sub.2-6 alkoxy) group or a group of the general formula:
-A-R.sup.8 in which A represents a single bond, an oxygen atom, a
methylene group, an ethylene group, --OCH.sub.2-- or --CH.sub.2O--;
and R.sup.8 represents a C.sub.3-7 cycloalkyl group, a C.sub.2-6
heterocycloalkyl group, an aryl group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group, an amino group, a C.sub.1-6 alkyl
group, a C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy group, a
halo(C.sub.1-6 alkyl) group, a hydroxy(C.sub.1-6 alkyl) group, a
carboxy group, a C.sub.2-7 alkoxycarbonyl group, a cyano group and
a nitro group, or a heteroaryl group which may have a substituent
selected from the group consisting of a halogen atom and a
C.sub.1-6 alkyl group;
X represents a single bond, an oxygen atom or a sulfur atom;
Y represents a single bond, a C.sub.1-6 alkylene group or a
C.sub.2-6 alkenylene group with the proviso that X is a single bond
when Y is a single bond;
Z represents a carbonyl group or a sulfonyl group;
R.sup.4 and R.sup.5 are the same or different, and each represents
a hydrogen atom or a C.sub.1-6 alkyl group which may have the same
or different 1 to 3 groups selected from the following substituent
group (i), or they bind together with the neighboring nitrogen atom
to form a C.sub.2-6 cyclic amino group which may have a substituent
selected from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group;
R.sup.3, R.sup.6 and R.sup.7 are the same or different, and each
represents a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group
or a C.sub.1-6 alkoxy group; and
substituent group (i) consists of a hydroxy group, an amino group,
a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a
sulfamide group, a mono or di(C.sub.1-6 alkyl)ureido group, a mono
or di(C.sub.1-6 alkyl)sulfamide group, a C.sub.2-7 acylamino group,
a C.sub.1-6 alkylsulfonylamino group, a group of the general
formula: --CON(R.sup.9)R.sup.10 in which R.sup.9 and R.sup.10 are
the same or different, and each represents a hydrogen atom or a
C.sub.1-6 alkyl group which may have the same or different 1 to 3
substituents selected from the group consisting of a hydroxy group,
an amino group, a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a mono or
di(C.sub.1-6 alkyl)ureido group, a C.sub.2-7 acylamino group, a
C.sub.1-6 alkylsulfonylamino group and a carbamoyl group, or they
bind together with the neighboring nitrogen atom to form a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, a C.sub.3-7 cycloalkyl group, a
C.sub.2-6 heterocycloalkyl group, an aryl group which may have the
same or different 1 to 3 substituents selected from the group
consisting of a halogen atom, a hydroxy group, an amino group, a
C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group, a heteroaryl
group which may have a substituent selected from the group
consisting of a halogen atom and a C.sub.1-6 alkyl group, a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, and a C.sub.1-4 aromatic cyclic
amino group which may have a C.sub.1-6 alkyl group as a
substituent, or a pharmaceutically acceptable salt thereof;
[2] a pyrazole derivative described in the above [1] wherein Y
represents a C.sub.1-6 alkylene group or a C.sub.2-6 alkenylene
group; one of R.sup.4 and R.sup.5 represents a C.sub.1-6 alkyl
group which has the same or different 1 to 3 groups selected from
the following substituent group (i), the other represents a
hydrogen atom or a C.sub.1-6 alkyl group which may have the same or
different 1 to 3 groups selected from the following substituent
group (i); and substituent group (i) consists of a hydroxy group,
an amino group, a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a
sulfamide group, a mono or di(C.sub.1-6 alkyl)ureido group, a mono
or di(C.sub.1-6 alkyl)sulfamide group, a C.sub.2-7 acylamino group,
a C.sub.1-6 alkylsulfonylamino group, a group of the general
formula: --CON(R.sup.9)R.sup.10 in which R.sup.9 and R.sup.10 are
the same or different, and each represents a hydrogen atom or a
C.sub.1-6 alkyl group which may have the same or different 1 to 3
substituents selected from the group consisting of a hydroxy group,
an amino group, a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a mono or
di(C.sub.1-6 alkyl)ureido group, a C.sub.2-7 acylamino group, a
C.sub.1-6 alkylsulfonylamino group and a carbamoyl group, or they
bind together with the neighboring nitrogen atom to form a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, a C.sub.3-7 cycloalkyl group, a
C.sub.2-6 heterocycloalkyl group, an aryl group which may have the
same or different 1 to 3 substituents selected from the group
consisting of a halogen atom, a hydroxy group, an amino group, a
C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group, a heteroaryl
group which may have a substituent selected from the group
consisting of a halogen atom and a C.sub.1-6 alkyl group, a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, and a C.sub.1-4 aromatic cyclic
amino group which may have a C.sub.1-6 alkyl group as a
substituent, or a pharmaceutically acceptable salt thereof;
[3] a pyrazole derivative described in the above [2] wherein one of
R.sup.4 and R.sup.5 represents a C.sub.1-6 alkyl group which has a
group selected from the following substituent group (iA), the other
represents a hydrogen atom; and substituent group (iA) is a group
of the general formula: --CON(R.sup.9A)R.sup.10A in which R.sup.9A
and R.sup.10A bind together with the neighboring nitrogen atom to
form a C.sub.2-6 cyclic amino group which may have a substituent
selected from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, or a pharmaceutically acceptable
salt thereof;
[4] a pyrazole derivative described in any one of the above [1]-[3]
wherein X represents a single bond; and Y represents a trimethylene
group or a 1-propenylene group, or a pharmaceutically acceptable
salt thereof;
[5] a pyrazole derivative described in any one of the above [1]-[3]
wherein X represents an oxygen atom; and Y represents an ethylene
group or a trimethylene group, or a pharmaceutically acceptable
salt thereof;
[6] a pyrazole derivative described in the above [1] wherein X
represents a single bond; Y represents a single bond; one of
R.sup.4 and R.sup.5 represents a C.sub.1-6 alkyl group which has
the same or different 1 to 3 groups selected from the following
substituent group (iB), the other represents a hydrogen atom or a
C.sub.1-6 alkyl group which may have the same or different 1 to 3
groups selected from the following substituent group (iB); and
substituent group (iB) consists of an ureido group, a sulfamide
group, a mono or di(C.sub.1-6 alkyl)ureido group, a mono or
di(C.sub.1-6 alkyl)sulfamide group, a C.sub.1-6 alkylsulfonylamino
group, a group of the general formula: --CON(R.sup.9B)R.sup.10B in
which one of R.sup.9B and R.sup.10B represents a C.sub.1-6 alkyl
group which has the same or different 1 to 3 substituents selected
from the group consisting of a hydroxy group, an amino group, a
mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a mono or
di(C.sub.1-6 alkyl)ureido group, a C.sub.2-7 acylamino group, a
C.sub.1-6 alkylsulfonylamino group and a carbamoyl group, the other
represents a hydrogen atom, a C.sub.1-6 alkyl group which may have
the same or different 1 to 3 substituents selected from the group
consisting of a hydroxy group, an amino group, a mono or
di(C.sub.1-6 alkyl)amino group, a mono or di[hydroxy(C.sub.1-6
alkyl)]amino group, an ureido group, a mono or di(C.sub.1-6
alkyl)ureido group, a C.sub.2-7 acylamino group, a C.sub.1-6
alkylsulfonylamino group and a carbamoyl group, or they bind
together with the neighboring nitrogen atom to form a C.sub.2-6
cyclic amino group which may have a substituent selected from the
group consisting of a C.sub.1-6 alkyl group and a hydroxy(C.sub.1-6
alkyl) group, a C.sub.3-7 cycloalkyl group, a C.sub.2-6
heterocycloalkyl group, an aryl group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group, an amino group, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group, a heteroaryl group which may
have a substituent selected from the group consisting of a halogen
atom and a C.sub.1-6 alkyl group, a C.sub.2-6 cyclic amino group
which may have a substituent selected from the group consisting of
a C.sub.1-6 alkyl group and a hydroxy(C.sub.1-6 alkyl) group, and a
C.sub.1-4 aromatic cyclic amino group which may have a C.sub.1-6
alkyl group as a substituent, or a pharmaceutically acceptable salt
thereof;
[7] a pyrazole derivative described in any one of the above [1]-[6]
wherein R.sup.1 represents a hydrogen atom or a hydroxy(C.sub.2-6
alkyl) group; T represents a group represented by the formula:
##STR00007## or a group represented by the formula:
##STR00008## Q represents a C.sub.1-6 alkyl group or a
halo(C.sub.1-6 alkyl) group; and R.sup.3, R.sup.6 and R.sup.7
represent a hydrogen atom, or a pharmaceutically acceptable salt
thereof;
[8] a pyrazole derivative described in any one of the above [1]-[6]
wherein one of Q and T represents a group represented by the
formula:
##STR00009## the other represents a C.sub.1-6 alkyl group, a
halo(C.sub.1-6 alkyl) group, a C.sub.1-6 alkoxy-substituted
(C.sub.1-6 alkyl) group or a C.sub.3-7 cycloalkyl group, or a
pharmaceutically acceptable salt thereof;
[9] a pyrazole derivative described in the above [7] or [8] wherein
T represents a group represented by the formula:
##STR00010## or a pharmaceutically acceptable salt thereof;
[10] a pyrazole derivative described in the above [7] or [9]
wherein Q represents an isopropyl group, or a pharmaceutically
acceptable salt thereof;
[11] a prodrug of a pyrazole derivative described in any one of the
above [1]-[10] or a pharmaceutically acceptable salt thereof;
[12] a prodrug described in the above [11] wherein T represents a
group represented by the formula:
##STR00011## or a group represented by the formula:
##STR00012## in which the hydroxy group at the 4-position is
substituted by a glucopyranosyl group or a galactopyranosyl group,
or the hydroxy group at the 6-position is substituted by a
glucopyranosyl group, a galactopyranosyl group, a C.sub.2-7 acyl
group, a C.sub.1-6 alkoxy-substituted (C.sub.2-7 acyl) group, a
C.sub.2-7 alkoxycarbonyl-substituted (C.sub.2-7 acyl) group, a
C.sub.2-7 alkoxycarbonyl group, an aryl(C.sub.2-7 alkoxycarbonyl)
group or a C.sub.1-6 alkoxy-substituted (C.sub.2-7 alkoxycarbonyl)
group;
[13] a pyrazole derivative described in the above [1] which is a
compound selected from the following group:
4-[(4-{3-[1-carbamoyl-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)me-
thyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperaz-
in-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]-propyl}phenyl)methyl]-5-isopr-
opyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[2-(dimethylamin-
o)ethylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyraz-
ole;
4-[(4-{3-[1-(2-aminoethylcarbamoyl)-1-(methyl)-ethylcarbamoyl]propyl}-
phenyl)methyl]-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]-propyl}-2-methylphenyl)methyl]--
5-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpipera-
zin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyra-
zole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-isoprop-
ylpiperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)-ethylca-
rbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{(1E)-3-[(S)-2-hydroxy-1-(methyl)-et-
hylcarbamoyl]prop-1-enyl}phenyl)methyl]-5-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}--
1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)-ethylc-
arbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)c-
arbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-1H-pyraz-
ole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1--
yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)-2-methylphenyl]methyl}-1H-p-
yrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]--
5-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-1-(3-hydroxypropyl)-5-isopropyl-4-{[4-(3-
-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]met-
hyl}-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-1H-py-
razole;
4-{[2-fluoro-4-(3-{(1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylc-
arbamoyl}propyl)phenyl]methyl}-3-(.beta.-D-galactopyranosyloxy)-5-isopropy-
l-1H-pyrazole;
4-{[2-chloro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl-
}propyl)phenyl]methyl}-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyraz-
ole, and pharmaceutically acceptable salts thereof;
[14] a pyrazole derivative described in the above [13] which is a
compound selected from the following group:
3-(.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperaz-
in-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]-propyl}phenyl)methyl]-5-isopr-
opyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]-propyl}-2-methylphenyl)methyl]--
5-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpipera-
zin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyra-
zole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpip-
erazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]met-
hyl}-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)c-
arbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-1H-pyraz-
ole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1--
yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)-2-methylphenyl]methyl}-1H-p-
yrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-1H-py-
razole;
4-{[2-fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylca-
rbamoyl}propyl)phenyl]methyl}-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-
-1H-pyrazole, and pharmaceutically acceptable salts thereof;
[15] a pharmaceutical composition comprising as an active
ingredient a pyrazole derivative described in any one of the above
[1]-[14], a pharmaceutically acceptable salt thereof or a prodrug
thereof;
[16] a human SGLT1 inhibitor comprising as an active ingredient a
pyrazole derivative described in any one of the above [1]-[14], a
pharmaceutically acceptable salt thereof or a prodrug thereof;
[17] an agent for inhibiting postprandial hyperglycemia comprising
as an active ingredient a pyrazole derivative described in any one
of the above [1]-[14], a pharmaceutically acceptable salt thereof
or a prodrug thereof;
[18] an agent for the prevention or treatment of a disease
associated with hyperglycemia, which comprises as an active
ingredient a pyrazole derivative described in any one of the above
[1]-[14], a pharmaceutically acceptable salt thereof or a prodrug
thereof;
[19] an agent for the prevention or treatment described in the
above [18] wherein the disease associated with hyperglycemia is a
disease selected from the group consisting of diabetes, impaired
glucose tolerance, diabetic complications, obesity,
hyperinsulinemia, hyperlipidemia, hyper-cholesterolemia,
hypertriglyceridemia, lipid metabolism disorder, atherosclerosis,
hypertension, congestive heart failure, edema, hyperuricemia and
gout;
[20] an agent for the inhibition of advancing impaired glucose
tolerance or impaired fasting glycemia into diabetes in a subject,
which comprises as an active ingredient a pyrazole derivative
described in any one of the above [1]-[14], a pharmaceutically
acceptable salt thereof or a prodrug thereof;
[21] an agent for the prevention or treatment of a disease
associated with the increase of blood galactose level, which
comprises as an active ingredient a pyrazole derivative described
in any one of the above [1]-[14], a pharmaceutically acceptable
salt thereof or a prodrug thereof;
[22] an agent for the prevention or treatment described in the
above [21] wherein the disease associated with the increase of
blood galactose level is galactosemia;
[23] a pharmaceutical composition described in the above [15]
wherein the dosage form is sustained release formulation;
[24] an agent described in any one of the above [16]-[22] wherein
the dosage form is sustained release formulation;
[25] a method for the prevention or treatment of a disease
associated with hyperglycemia, which comprises administering an
effective amount of a pyrazole derivative described in any one of
the above [1]-[14], a pharmaceutically acceptable salt thereof or a
prodrug thereof;
[26] a method for the inhibition of advancing impaired glucose
tolerance into diabetes in a subject, which comprises administering
an effective amount of a pyrazole derivative described in any one
of the above [1]-[14], a pharmaceutically acceptable salt thereof
or a prodrug thereof;
[27] a use of a pyrazole derivative described in any one of the
above [1]-[14], a pharmaceutically acceptable salt thereof or a
prodrug thereof for the manufacture of a pharmaceutical composition
for the prevention or treatment of a disease associated with
hyperglycemia;
[28] a use of a pyrazole derivative described in any one of the
above [1]-[14], a pharmaceutically acceptable salt thereof or a
prodrug thereof for the manufacture of a pharmaceutical composition
for the inhibition of advancing impaired glucose tolerance into
diabetes in a subject;
[29] a pharmaceutical combination which comprises (A) a pyrazole
derivative described in any one of the above [1]-[14], a
pharmaceutically acceptable salt thereof or a prodrug thereof, and
(B) at least one member selected from the group consisting of an
insulin sensitivity enhancer, a glucose absorption inhibitor, a
biguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an
insulin or insulin analogue, a glucagon receptor antagonist, an
insulin receptor kinase stimulant, a tripeptidyl peptidase II
inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine
phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a
glucose-6-phosphatase inhibitor, a fructose-bisphosphatase
inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic
gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase
kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like
peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an
amylin analogue, an amylin agonist, an aldose reductase inhibitor,
an advanced glycation end products formation inhibitor, a protein
kinase C inhibitor, a .gamma.-amino butyric acid receptor
antagonist, a sodium channel antagonist, a transcript factor
NF-.kappa.B inhibitor, a lipid peroxidase inhibitor, an
N-acetylated-.alpha.-linked-acid-dipeptidase inhibitor,
insulin-like growth factor-I, platelet-derived growth factor, a
platelet-derived growth factor analogue, epidermal growth factor,
nerve growth factor, a carnitine derivative, uridine,
5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide,
Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme
A reductase inhibitor, a fibric acid derivative, a
.beta..sub.3-adrenoceptor agonist, an acyl-coenzyme A cholesterol
acyltransferase inhibitor, probcol, a thyroid hormone receptor
agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a
microsomal triglyceride transfer protein inhibitor, a lipoxygenase
inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene
synthase inhibitor, a low-density lipoprotein receptor enhancer, a
nicotinic acid derivative, a bile acid sequestrant, a sodium/bile
acid cotransporter inhibitor, a cholesterol ester transfer protein
inhibitor, an appetite suppressant, an angiotensin-converting
enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin
II receptor antagonist, an endothelin-converting enzyme inhibitor,
an endothelin receptor antagonist, a diuretic agent, a calcium
antagonist, a vasodilating antihypertensive agent, a sympathetic
blocking agent, a centrally acting antihypertensive agent, an
.alpha..sub.2-adrenoceptor agonist, an antiplatelets agent, a uric
acid synthesis inhibitor, a uricosuric agent and a urinary
alkalinizer;
[30] a method for the prevention or treatment of a disease
associated with hyperglycemia, which comprises administering an
effective amount of (A) a pyrazole derivative described in any one
of the above [1]-[14], a pharmaceutically acceptable salt thereof
or a prodrug thereof, and (B) at least one member selected from the
group consisting of an insulin sensitivity enhancer, a glucose
absorption inhibitor, a biguanide, an insulin secretion enhancer, a
SGLT2 inhibitor, an insulin or insulin analogue, a glucagon
receptor antagonist, an insulin receptor kinase stimulant, a
tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV
inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen
phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a
fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase
inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a
glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a
glucagon-like peptide-1 analogue, a glucagon-like peptide-1
agonist, amylin, an amylin analogue, an amylin agonist, an aldose
reductase inhibitor, an advanced glycation endproducts formation
inhibitor, a protein kinase C inhibitor, a .gamma.-aminobutyric
acid receptor antagonist, a sodium channel antagonist, a transcript
factor NF-.kappa.B inhibitor, a lipid peroxidase inhibitor, an
N-acetylated-.alpha.-linked-acid-dipeptidase inhibitor,
insulin-like growth factor-I, platelet-derived growth factor, a
platelet-derived growth factor analogue, epidermal growth factor,
nerve growth factor, a carnitine derivative, uridine,
5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide,
Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme
A reductase inhibitor, a fibric acid derivative, a
.beta..sub.3-adrenoceptor agonist, an acyl-coenzyme A cholesterol
acyltransferase inhibitor, probcol, a thyroid hormone receptor
agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a
microsomal triglyceride transfer protein inhibitor, a lipoxygenase
inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene
synthase inhibitor, a low-density lipoprotein receptor enhancer, a
nicotinic acid derivative, a bile acid sequestrant, a sodium/bile
acid cotransporter inhibitor, a cholesterol ester transfer protein
inhibitor, an appetite suppressant, an angiotensin-converting
enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin
II receptor antagonist, an endothelin-converting enzyme inhibitor,
an endothelin receptor antagonist, a diuretic agent, a calcium
antagonist, a vasodilating antihypertensive agent, a sympathetic
blocking agent, a centrally acting antihypertensive agent, an
.alpha..sub.2-adrenoceptor agonist, an antiplatelets agent, a uric
acid synthesis inhibitor, a uricosuric agent and a urinary
alkalinizer;
[31] a method for the inhibition of advancing impaired glucose
tolerance into diabetes in a subject, which comprises administering
an effective amount of (A) a pyrazole derivative described in any
one of the above [1]-[14], a pharmaceutically acceptable salt
thereof or a prodrug thereof, and (B) at least one member selected
from the group consisting of an insulin sensitivity enhancer, a
glucose absorption inhibitor, a biguanide, an insulin secretion
enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, a
glucagon receptor antagonist, an insulin receptor kinase stimulant,
a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV
inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen
phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a
fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase
inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a
glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a
glucagon-like peptide-1 analogue, a glucagon-like peptide-1
agonist, amylin, an amylin analogue, an amylin agonist, an aldose
reductase inhibitor, an advanced glycation endproducts formation
inhibitor, a protein kinase C inhibitor, a .gamma.-aminobutyric
acid receptor antagonist, a sodium channel antagonist, a transcript
factor NF-.kappa.B inhibitor, a lipid peroxidase inhibitor, an
N-acetylated-.alpha.-linked-acid-dipeptidase inhibitor,
insulin-like growth factor-I, platelet-derived growth factor, a
platelet-derived growth factor analogue, epidermal growth factor,
nerve growth factor, a carnitine derivative, uridine,
5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide,
Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme
A reductase inhibitor, a fibric acid derivative, a
.beta..sub.3-adrenoceptor agonist, an acyl-coenzyme A cholesterol
acyltransferase inhibitor, probcol, a thyroid hormone receptor
agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a
microsomal triglyceride transfer protein inhibitor, a lipoxygenase
inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene
synthase inhibitor, a low-density lipoprotein receptor enhancer, a
nicotinic acid derivative, a bile acid sequestrant, a sodium/bile
acid cotransporter inhibitor, a cholesterol ester transfer protein
inhibitor, an appetite suppressant, an angiotensin-converting
enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin
II receptor antagonist, an endothelin-converting enzyme inhibitor,
an endothelin receptor antagonist, a diuretic agent, a calcium
antagonist, a vasodilating antihypertensive agent, a sympathetic
blocking agent, a centrally acting antihypertensive agent, an
.alpha..sub.2-adrenoceptor agonist, an antiplatelets agent, a uric
acid synthesis inhibitor, a uricosuric agent and a urinary
alkalinizer;
[32] a use of (A) a pyrazole derivative described in any one of the
above [1]-[14], a pharmaceutically acceptable salt thereof or a
prodrug thereof, and (B) at least one member selected from the
group consisting of an insulin sensitivity enhancer, a glucose
absorption inhibitor, a biguanide, an insulin secretion enhancer, a
SGLT2 inhibitor, an insulin or insulin analogue, a glucagon
receptor antagonist, an insulin receptor kinase stimulant, a
tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV
inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen
phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a
fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase
inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a
glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a
glucagon-like peptide-1 analogue, a glucagon-like peptide-1
agonist, amylin, an amylin analogue, an amylin agonist, an aldose
reductase inhibitor, an advanced glycation endproducts formation
inhibitor, a protein kinase C inhibitor, a .gamma.-aminobutyric
acid receptor antagonist, a sodium channel antagonist, a transcript
factor NF-.kappa.B inhibitor, a lipid peroxidase inhibitor, an
N-acetylated-.alpha.-linked-acid-dipeptidase inhibitor,
insulin-like growth factor-I, platelet-derived growth factor, a
platelet-derived growth factor analogue, epidermal growth factor,
nerve growth factor, a carnitine derivative, uridine,
5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide,
Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme
A reductase inhibitor, a fibric acid derivative, a
.beta..sub.3-adrenoceptor agonist, an acyl-coenzyme A cholesterol
acyltransferase inhibitor, probcol, a thyroid hormone receptor
agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a
microsomal triglyceride transfer protein inhibitor, a lipoxygenase
inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene
synthase inhibitor, a low-density lipoprotein receptor enhancer, a
nicotinic acid derivative, a bile acid sequestrant, a sodium/bile
acid cotransporter inhibitor, a cholesterol ester transfer protein
inhibitor, an appetite suppressant, an angiotensin-converting
enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin
II receptor antagonist, an endothelin-converting enzyme inhibitor,
an endothelin receptor antagonist, a diuretic agent, a calcium
antagonist, a vasodilating antihypertensive agent, a sympathetic
blocking agent, a centrally acting antihypertensive agent, an
.alpha..sub.2-adrenoceptor agonist, an antiplatelets agent, a uric
acid synthesis inhibitor, a uricosuric agent and a urinary
alkalinizer, for the manufacture of a pharmaceutical composition
for the prevention or treatment of a disease associated with
hyperglycemia;
[33] a use of (A) a pyrazole derivative described in any one of the
above [1]-[14], a pharmaceutically acceptable salt thereof or a
prodrug thereof, and (B) at least one member selected from the
group consisting of an insulin sensitivity enhancer, a glucose
absorption inhibitor, a biguanide, an insulin secretion enhancer, a
SGLT2 inhibitor, an insulin or insulin analogue, a glucagon
receptor antagonist, an insulin receptor kinase stimulant, a
tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV
inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen
phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a
fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase
inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a
glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a
glucagon-like peptide-1 analogue, a glucagon-like peptide-1
agonist, amylin, an amylin analogue, an amylin agonist, an aldose
reductase inhibitor, an advanced glycation endproducts formation
inhibitor, a protein kinase C inhibitor, a .gamma.-aminobutyric
acid receptor antagonist, a sodium channel antagonist, a transcript
factor NF-.kappa.B inhibitor, a lipid peroxidase inhibitor, an
N-acetylated-.alpha.-linked-acid-dipeptidase inhibitor,
insulin-like growth factor-I, platelet-derived growth factor, a
platelet-derived growth factor analogue, epidermal growth factor,
nerve growth factor, a carnitine derivative, uridine,
5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide,
Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme
A reductase inhibitor, a fibric acid derivative, a
.beta..sub.3-adrenoceptor agonist, an acyl-coenzyme A cholesterol
acyltransferase inhibitor, probcol, a thyroid hormone receptor
agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a
microsomal triglyceride transfer protein inhibitor, a lipoxygenase
inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene
synthase inhibitor, a low-density lipoprotein receptor enhancer, a
nicotinic acid derivative, a bile acid sequestrant, a sodium/bile
acid cotransporter inhibitor, a cholesterol ester transfer protein
inhibitor, an appetite suppressant, an angiotensin-converting
enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin
II receptor antagonist, an endothelin-converting enzyme inhibitor,
an endothelin receptor antagonist, a diuretic agent, a calcium
antagonist, a vasodilating antihypertensive agent, a sympathetic
blocking agent, a centrally acting antihypertensive agent, an
.alpha..sub.2-adrenoceptor agonist, an antiplatelets agent, a uric
acid synthesis inhibitor, a uricosuric agent and a urinary
alkalinizer, for the manufacture of a pharmaceutical composition
for the inhibition of advancing impaired glucose tolerance into
diabetes in a subject;
[34] a pyrazole derivative represented by the general formula:
##STR00013## wherein
R.sup.11 represents a hydrogen atom, a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a hydroxy(C.sub.2-6 alkyl) group which may
have a protective group, a C.sub.3-7 cycloalkyl group, a C.sub.3-7
cycloalkyl-substituted (C.sub.1-6 alkyl) group, an aryl group which
may have the same or different 1 to 3 substituents selected from
the group consisting of a halogen atom, a hydroxy group which may
have a protective group, an amino group which may have a protective
group, a C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group, or an
aryl(C.sub.1-16 alkyl) group which may have the same or different 1
to 3 substituents selected from the group consisting of a halogen
atom, a hydroxy group which may have a protective group, an amino
group which may have a protective group, a C.sub.1-6 alkyl group
and a C.sub.1-6 alkoxy group on the ring;
one of Q.sup.2 and T.sup.2 represents a
2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy group or a
2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy group, while
the other represents a C.sub.1-6 alkyl group, a halo(C.sub.1-6
alkyl) group, a C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkyl)
group or a C.sub.3-7 cycloalkyl group;
R.sup.12 represents a hydrogen atom, a halogen atom, a hydroxy
group which may have a protective group, a C.sub.1-6 alkyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkylthio group, a
halo(C.sub.1-6 alkyl) group, a halo(C.sub.1-6 alkoxy) group, a
C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkoxy) group, a C.sub.3-7
cycloalkyl-substituted (C.sub.2-6 alkoxy) group or a group of the
general formula: -A-R.sup.18 in which A represents a single bond,
an oxygen atom, a methylene group, an ethylene group, --OCH.sub.2--
or --CH.sub.2O--; and R.sup.18 represents a C.sub.3-7 cycloalkyl
group, a C.sub.2-6 heterocycloalkyl group, an aryl group which may
have the same or different 1 to 3 substituents selected from the
group consisting of a halogen atom, a hydroxy group which may have
a protective group, an amino group which may have a protective
group, a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a
C.sub.2-6 alkenyloxy group, a halo(C.sub.1-6 alkyl) group, a
hydroxy(C.sub.1-6 alkyl) group which may have a protective group, a
carboxy group which may have a protective group, a C.sub.2-7
alkoxycarbonyl group, a cyano group and a nitro group, or a
heteroaryl group which may have a substituent selected from the
group consisting of a halogen atom and a C.sub.1-6 alkyl group;
X represents a single bond, an oxygen atom or a sulfur atom;
Y represents a single bond, a C.sub.1-6 alkylene group or a
C.sub.2-6 alkenylene group with the proviso that X is a single bond
when Y is a single bond;
Z represents a carbonyl group or a sulfonyl group;
R.sup.14 and R.sup.15 are the same or different, and each
represents a hydrogen atom or a C.sub.1-6 alkyl group which may
have the same or different 1 to 3 groups selected from the
following substituent group (ii), or they bind together with the
neighboring nitrogen atom to form a C.sub.2-6 cyclic amino group
which may have a substituent selected from the group consisting of
a C.sub.1-6 alkyl group and a hydroxy(C.sub.1-6 alkyl) group which
may have a protective group;
R.sup.3, R.sup.6 and R.sup.7 are the same or different, and each
represents a hydrogen atom, a halogen atom, a C.sub.1-6 alkyl group
or a C.sub.1-6 alkoxy group; and
substituent group (ii) consists of a hydroxy group which may have a
protective group, an amino group which may have a protective group,
a mono or di(C.sub.1-6 alkyl)amino group which may have a
protective group, a mono or di[hydroxy(C.sub.1-6 alkyl)]amino group
which may have a protective group, an ureido group, a sulfamide
group, a mono or di(C.sub.1-6 alkyl)ureido group, a mono or
di(C.sub.1-6 alkyl)sulfamide group, a C.sub.2-7 acylamino group, a
C.sub.1-6 alkylsulfonylamino group, a group of the general formula:
--CON(R.sup.19)R.sup.20 in which R.sup.19 and R.sup.20 are the same
or different, and each represents a hydrogen atom or a C.sub.1-6
alkyl group which may have the same or different 1 to 3
substituents selected from the group consisting of a hydroxy group
which may have a protective group, an amino group which may have a
protective group, a mono or di(C.sub.1-6 alkyl)amino group which
may have a protective group, a mono or di[hydroxy(C.sub.1-6
alkyl)]amino group which may have a protective group, an ureido
group, a mono or di(C.sub.1-6 alkyl)ureido group, a C.sub.2-7
acylamino group, a C.sub.1-6 alkylsulfonylamino group and a
carbamoyl group, or they bind together with the neighboring
nitrogen atom to form a C.sub.2-6 cyclic amino group which may have
a substituent selected from the group consisting of a C.sub.1-6
alkyl group and a hydroxy(C.sub.1-6 alkyl) group which may have a
protective group, a C.sub.3-7 cycloalkyl group, a C.sub.2-6
heterocycloalkyl group, an aryl group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group which may have a protective group,
an amino group which may have a protective group, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group, a heteroaryl group which may
have a substituent selected from the group consisting of a halogen
atom and a C.sub.1-6 alkyl group, a C.sub.2-6 cyclic amino group
which may have a substituent selected from the group consisting of
a C.sub.1-6 alkyl group and a hydroxy(C.sub.1-6 alkyl) group which
may have a protective group, and a C.sub.1-4 aromatic cyclic amino
group which may have a C.sub.1-6 alkyl group as a substituent, or a
salt thereof; and the like.
In the present invention, the term "C.sub.1-6 alkyl group" means a
straight-chained or branched alkyl group having 1 to 6 carbon atoms
such as a methyl group, an ethyl group, a propyl group, an
isopropyl group, a butyl group, an isobutyl group, a sec-butyl
group, a tert-butyl group, a pentyl group, an isopentyl group, a
neopentyl group, a tert-pentyl group, a hexyl group or the like;
the term "C.sub.1-6 alkylene group" means a straight-chained or
branched alkylene group having 1 to 6 carbon atoms such as a
methylene group, an ethylene group, a trimethylene group, a
tetramethylene group, a propylene group, a 1,1-dimethylethylene
group or the like; the term "hydroxy(C.sub.1-6 alkyl) group" means
the above C.sub.1-6 alkyl group substituted by a hydroxy group; the
term "C.sub.2-6 alkyl group" means a straight-chained or branched
alkyl group having 2 to 6 carbon atoms such as an ethyl group, a
propyl group, an isopropyl group, a butyl group, an isobutyl group,
a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl
group, a neopentyl group, a tert-pentyl group, a hexyl group or the
like; the term "hydroxy(C.sub.2-6 alkyl) group" means the above
C.sub.2-6 alkyl group substituted by a hydroxy group, such as a
2-hydroxyethyl group, a 3-hydroxypropyl group or the like; the term
"C.sub.1-6 alkoxy group" means a straight-chained or branched
alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an
ethoxy group, a propoxy group, an isopropoxy group, a butoxy group,
an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a
pentyloxy group, an isopentyloxy group, a neopentyloxy group, a
tert-pentyloxy group, a hexyloxy group or the like; the term
"C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkyl) group" means the
above C.sub.1-6 alkyl group substituted by the above C.sub.1-6
alkoxy group; the term "C.sub.1-6 alkoxy-substituted (C.sub.1-6
alkoxy) group" means the above C.sub.1-6 alkoxy group substituted
by the above C.sub.1-6 alkoxy group, such as a methoxymethoxy group
or the like; the term "C.sub.2-6 alkenyl group" means a
straight-chained or branched alkenyl group having 2 to 6 carbon
atoms such as a vinyl group, an allyl group, a 1-propenyl group, an
isopropenyl group, a 1-butenyl group, a 2-butenyl group, a
2-methylallyl group or the like; the term "C.sub.2-6 alkenylene
group" means a straight-chained or branched alkenylene group having
2 to 6 carbon atoms such as a vinylene group, a propenylene group
or the like; the term "C.sub.2-6 alkenyloxy group" means the above
C.sub.1-6 alkoxy group except for a methoxy group which has an
unsaturated bond, such as an allyloxy group or the like; the term
"C.sub.1-6 alkylthio group" means a straight-chained or branched
alkylthio group having 1 to 6 carbon atoms such as a methylthio
group, an ethylthio group, a propylthio group, an isopropylthio
group, a butylthio group, an isobutylthio group, a sec-butylthio
group, a tert-butylthio group, a pentylthio group, an isopentylthio
group, a neopentylthio group, a tert-pentylthio group, a hexylthio
group or the like; the term "mono or di(C.sub.1-6 alkyl)amino
group" means an amino group mono-substituted by the above C.sub.1-6
alkyl group or di-substituted by the same or different C.sub.1-6
alkyl groups as defined above; the term "mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group" means an amino group
mono-substituted by the above hydroxy(C.sub.1-6 alkyl) group or
di-substituted by the same or different hydroxy(C.sub.1-6 alkyl)
groups as defined above; the term "mono or di(C.sub.1-6
alkyl)ureido group" means an ureido group mono-substituted by the
above C.sub.1-6 alkyl group or di-substituted by the same or
different C.sub.1-6 alkyl groups as defined above; the term "mono
or di(C.sub.1-6 alkyl)sulfamide group" means a sulfamide group
mono-substituted by the above C.sub.1-6 alkyl group or
di-substituted by the same or different C.sub.1-6 alkyl groups as
defined above; the term "C.sub.2-7 acylamino group" means an amino
group substituted by a straight-chained or branched acyl group
having 2 to 7 carbon atoms such as an acetyl group, a propionyl
group, a butyryl group, an isobutyryl group, a valeryl group, a
pivaloyl group, a hexanoyl group or the like; the term "C.sub.1-6
alkylsulfonylamino group" means an amino group substituted by a
straight-chained or branched alkylsulfonyl group having 1 to 6
carbon atoms, such as a methanesulfonyl group, an ethanesulfonyl
group or the like; the term "C.sub.3-7 cycloalkyl group" means a
cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a
cyclohexyl group or a cycloheptyl group; the term "C.sub.3-7
cycloalkyl-substituted (C.sub.1-6 alkyl) group" means the above
C.sub.1-6 alkyl group substituted by the above C.sub.3-7 cycloalkyl
group; the term "C.sub.3-7 cycloalkyl-substituted (C.sub.2-6
alkoxy) group" means the above C.sub.1-6 alkoxy group except for a
methoxy group substituted by the above C.sub.3-7 cycloalkyl group;
the term "C.sub.2-6 heterocycloalkyl group" means the above
C.sub.3-7 cycloalkyl group containing the same or different 1 or 2
hetero atoms other than the binding position selected from a
nitrogen atom, an oxygen atom and a sulfur atom in the ring, which
is derived from morpholine, thiomorpholine, tetrahydrofuran,
tetrahydropyran, aziridine, azetidine, pyrrolidine, imidazolidine,
oxazoline, piperidine, piperazine, pyrazolidine or the like; the
term "halogen atom" means a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom; the term "halo(C.sub.1-6 alkyl)
group" means the above C.sub.1-6 alkyl group substituted by the
same or different 1 to 5 halogen atoms as defined above, such as a
trifluoromethyl group, a pentafluoroethyl group or the like; the
term "halo(C.sub.1-6 alkoxy) group" means the above C.sub.1-6
alkoxy group substituted by the same or different 1 to 5 halogen
atoms as defined above; the term "C.sub.2-7 alkoxycarbonyl group"
means a straight-chained or branched alkoxycarbonyl group having 2
to 7 carbon atoms such as a methoxycarbonyl group, an
ethoxycarbonyl group, a propoxycarbonyl group, an
isopropoxycarbonyl group, a butoxycarbonyl group, an
isobutyloxycarbonyl group, a sec-butoxycarbonyl group, a
tert-butoxycarbonyl group, a pentyloxycarbonyl group, an
isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a
tert-pentyloxycarbonyl group, a hexyloxycarbonyl group or the like;
the term "aryl group" means mono to tricyclic aromatic hydrocarbon
group such as a phenyl group, a naphthyl group, or the like; the
term "aryl(C.sub.1-6 alkyl) group" means the above C.sub.1-6 alkyl
group substitute by the above aryl group; the term "heteroaryl
group" means a 5 or 6-membered heteroaryl group containing the same
or different 1 to 4 hetero atoms other than the binding position
selected from a nitrogen atom, an oxygen atom and a sulfur atom in
the ring, which is derived from thiazole, oxazole, isothiazole,
isooxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole,
thiophene, imidazole, pyrazole, oxadiazole, thiodiazole, tetrazole,
furazan or the like; the term "C.sub.2-6 cyclic amino group" means
a 5 or 6-membered monocyclic amino group having 2 to 6 carbon atoms
which may contain one hetero atom other than the nitrogen atom at
the binding position selected from a nitrogen atom, an oxygen atom
and a sulfur atom in the ring, such as a morpholino group, a
thiomorpholino group, a 1-aziridinyl group, a 1-azetidinyl group, a
1-pyrrolidinyl group, a piperidino group, a 1-imidazolidinyl group,
a 1-piperazinyl group, a pyrazolidinyl group or the like; the term
"C.sub.1-4 aromatic cyclic amino group" means a 5-membered aromatic
monocyclic amino group having 1 to 4 carbon atoms which may contain
1 to 3 nitrogen atoms other than the nitrogen atom at the binding
position, such as a 1-imidazolyl group, a 1-pyrrolyl group, a
pyrazolyl group, a 1-tetrazolyl group or the like; the term
"hydroxy-protective group" means a hydroxy-protective group used in
general organic synthesis such as a benzyl group, a methoxymethyl
group, an acetyl group, a pivaloyl group, a benzoyl group, a
tert-butyldimethylsilyl group, a triisopropylsilyl group, an allyl
group or the like; the term "amino-protective group" means an
amino-protective group used in general organic synthesis such as a
benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl
group, a trifluoroacetyl group or the like; and the term
"carboxy-protective group" means a carboxy-protective group used in
general organic synthesis such as a benzyl group, a
tert-butyldimethylsilyl group, an allyl group or the like.
In the present invention, for example, R.sup.1 is preferably a
hydrogen atom or a hydroxy(C.sub.2-6 alkyl) group, and is more
preferably a hydrogen atom; T is preferably a group of the
formula:
##STR00014## or a group of the formula:
##STR00015## Q is preferably a C.sub.1-6 alkyl group or a
halo(C.sub.1-6 alkyl) group, and is more preferably a C.sub.1-6
alkyl group; the C.sub.1-6 alkyl group in Q is preferably an ethyl
group or an isopropyl group, and is more preferably an isopropyl
group; X is preferably a single bond or an oxygen atom.
Furthermore, when X is a single bond, Y is preferably a C.sub.1-6
alkylene group or a C.sub.2-6 alkenylene group, and is more
preferably a trimethylene group or a 1-propenylene group; and when
X is an oxygen atom, Y is preferably a C.sub.1-6 alkylene group,
and is more preferably an ethylene group or a trimethylene group. Z
is preferably a carbonyl group; R.sup.2 is preferably a hydrogen
atom, a halogen atom, a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy
group, a C.sub.1-6 alkoxy-substituted (C.sub.2-6 alkoxy) group, a
C.sub.3-7 cycloalkyl-substituted (C.sub.2-6 alkoxy) group or a
group of the general formula: -A-R.sup.8 in which A and R.sup.8
have the same meanings as defined above, and is more preferably a
hydrogen atom, a chlorine atom, a fluorine atom or a methyl group;
one of R.sup.4 and R.sup.5 is preferably a C.sub.1-6 alkyl group
which has 1 to 3 hydroxy groups or a group of the general formula:
--CON(R.sup.9)R.sup.10 in which R.sup.9 and R.sup.10 are the same
or different, and each represents a hydrogen atom or a C.sub.1-6
alkyl group which may have the same or different 1 to 3
substituents selected from the group consisting of a hydroxy group,
an amino group, a mono or di(C.sub.1-6 alkyl)amino group, a mono or
di[hydroxy(C.sub.1-6 alkyl)]amino group, an ureido group, a mono or
di(C.sub.1-6 alkyl)ureido group, a C.sub.2-7 acylamino group, a
C.sub.1-6 alkylsulfonylamino group and a carbamoyl group, or they
bind together with the neighboring nitrogen atom to form a
C.sub.2-6 cyclic amino group which may have a substituent selected
from the group consisting of a C.sub.1-6 alkyl group and a
hydroxy(C.sub.1-6 alkyl) group, while the other is preferably a
hydrogen atom, and one of R.sup.4 and R.sup.5 is more preferably a
C.sub.1-6 alkyl group which has a group of the general formula:
--CON(R.sup.9A)R.sup.10A in which R.sup.9A and R.sup.10A bind
together with the neighboring nitrogen atom to form a C.sub.2-6
cyclic amino group which may have a substituent selected from the
group consisting of a C.sub.1-6 alkyl group and a hydroxy(C.sub.1-6
alkyl) group, while the other is more preferably a hydrogen atom;
and R.sup.3, R.sup.6 and R.sup.7 are preferably a hydrogen atom or
a halogen atom, and all of them are more preferably a hydrogen
atom.
As concrete compounds in the present invention, compounds described
in Examples 1-116 are examplified. Specifically, the following
compounds or pharmaceutically acceptable salts thereof are
preferable,
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
and
3-(.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-pip-
erazin-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]-propyl}phenyl)methyl]-5-i-
sopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]-methyl}-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpipera-
zin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyra-
zole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpip-
erazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]met-
hyl}-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin-
-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)c-
arbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-1H-pyraz-
ole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1--
yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)-2-methylphenyl]methyl}-1H-p-
yrazole;
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazi-
n-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-
-1H-pyrazole;
3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl-
)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-1H-py-
razole;
4-{[2-fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylca-
rbamoyl}propyl)phenyl]methyl}-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-
-1H-pyrazole, or pharmaceutically acceptable salts thereof are more
preferable.
For example, the compounds represented by the above general formula
(I) of the present invention can be prepared according to the
following procedure:
##STR00021## wherein L.sup.1 represents a leaving group such as a
halogen atom, a mesyloxy group, a tosyloxy group or the like;
L.sup.2 represents MgBr, MgCl, MgI, ZnI, ZnBr, ZnCl or a lithium
atom; R represents a C.sub.1-6 alkyl group, a halo(C.sub.1-6 alkyl)
group, a C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkyl) group or a
C.sub.3-7 cycloalkyl group; R.sup.0 represents a C.sub.1-6 alkyl
group; one of Q.sup.3 and T.sup.3 represents a hydroxy group, the
other represents a C.sub.1-6 alkyl group, a halo(C.sub.1-6 alkyl)
group, a C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkyl) group or a
C.sub.3-7 cycloalkyl group; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.11, R.sup.12, R.sup.14, R.sup.15,
Q, Q.sup.2, T, T.sup.2, X, Y and Z have the same meanings as
defined above. Process 1-1
A compound represented by the above general formula (VI) can be
prepared by condensing a benzyl derivative represented by the above
general formula (IV) with a ketoacetate represented by the above
general formula (V) in the presence of a base such as sodium
hydride or potassium tert-butoxide in an inert solvent. As the
inert solvent used in the reaction, for example,
1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide, a
mixed solvent thereof and the like can be illustrated. The reaction
temperature is usually from room temperature to reflux temperature,
and the reaction time is usually from 1 hour to 1 day, varying
based on a used starting material, solvent and reaction
temperature.
Process 1-2
A benzylpyrazole derivative represented by the above general
formula (III) can be prepared by condensing a compound represented
by the above general formula (VI) with a hydrazine compound
represented by the above general formula (VII) or a monohydrate
thereof, or a salt thereof in the presence or absence of a base in
an inert solvent, and introducing a hydroxy-protective in usual way
as occasion demands. As the inert solvent used in the condensing
reaction, for example, toluene, tetrahydrofuran, chloroform,
methanol, ethanol, a mixed solvent thereof and the like can be
illustrated, and as that base, for example, triethylamine,
N,N-diisopropylethylamine, pyridine, sodium methoxide, sodium
ethoxide and the like can be illustrated. The reaction temperature
is usually from room temperature to reflux temperature, and the
reaction time is usually from 1 hour to 1 day, varying based on a
used starting material, solvent and reaction temperature. The
obtained benzylpyrazole derivative represented by the above general
formula (III) can be also used in the subsequent process after
suitably converting into a salt thereof in usual way.
Process 1-3
A compound represented by the above general formula (X) can be
prepared by condensing dithiocarbonate ester compound represented
by the above general formula (VIII) with a ketone compound
represented by the above general formula (IX) in the presence of a
base such as sodium amide in an inert solvent. As the inert solvent
used in the reaction, for example, toluene and the like can be
illustrated. The reaction temperature is usually from -20.degree.
C. to room temperature, and the reaction time is usually from 30
minutes to 1 day, varying based on a used starting material,
solvent and reaction temperature.
Process 1-4
A benzyloxypyrazole derivative represented by the above general
formula (XI) can be prepared by condensing a compound represented
by the above general formula (X) with a hydrazine compound
represented by the above general formula (VII) or a monohydrate
thereof, or a salt thereof in the presence of a base such as
triethylamine or N,N-diisopropylethylamine in an inert solvent, and
introducing a hydrogen-protective in usual way as occasion demands.
As the inert solvent used in the condensing reaction, for example,
acetonitrile and the like can be illustrated. The reaction
temperature is usually from 0.degree. C. to reflux temperature, and
the reaction time is usually from 1 hour to 1 day, varying based on
a used starting material, solvent and reaction temperature.
Process 1-5
A pyrazole aldehyde derivative represented by the above general
formula (XII) can be prepared by subjecting a compound represented
by the above general formula (XI) to Vilsmeier reaction using
phosphorus oxychloride and N,N-dimethylformamide in a various
solvent. As the solvent used in the reaction, for example,
N,N-dimethylformamide and the like can be illustrated. The reaction
temperature is usually from 0.degree. C. to reflux temperature, and
the reaction time is usually from 30 minutes to 1 day, varying
based on a used starting material, solvent and reaction
temperature.
Process 1-6
A compound represented by the above general formula (XIV) can be
prepared by condensing a compound represented by the above general
formula (XII) with a Grignard reagent, a Reformatsky reagent or a
lithium reagent represented by the above general formula (XIII) in
an inert solvent. As the solvent used in the reaction, for example,
tetrahydrofuran, diethyl ether, a mixed solvent thereof and the
like can be illustrated. The reaction temperature is usually from
-78.degree. C. to room temperature, and the reaction time is
usually from 30 minutes to 1 day, varying based on a used starting
material, solvent and reaction temperature.
Process 1-7
A benzylpyrazole derivative represented by the above general
formula (III) can be prepared by subjecting a compound represented
by the above general formula (XIV) to catalytic hydrogenation using
a palladium catalyst such as palladium-carbon powder in the
presence or absence of an acid such as hydrochloric acid in an
inert solvent, and in a case of a compound having any sulfur atom
represented by the above general formula (XIV), subjecting the
resulting compound to acid treatment in an aqueous solution of
trifluoroacetic acid and dimethyl sulfide usually at 0.degree. C.
to reflux temperature for 30 minutes to 1 day as occasion demands.
As the solvent used in the catalytic hydrogenation, for example,
methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid,
isopropanol, a mixed solvent thereof and the like can be
illustrated. The reaction temperature is usually from room
temperature to reflux temperature, and the reaction time is usually
from 30 minutes to 1 day, varying based on a used starting
material, solvent and reaction temperature. The obtained
benzylpyrazole derivative represented by the above general formula
(III) can be also used in the subsequent process after suitably
converting into a salt thereof in the usual way.
Process 1-8
[1] In case that one of Q.sup.3 and T.sup.3 is a C.sub.1-6 alkyl
group, a C.sub.1-6 alkoxy-substituted (C.sub.1-6 alkyl) group or a
C.sub.3-7 cycloalkyl group in a benzylpyrazole derivative
represented by the above general formula (III), a corresponding
compound represented by the above general formula (II) of the
present invention can be prepared by subjecting a corresponding
benzylpyrazole derivative represented by the above general formula
(III) to glycosidation using acetobromo-.alpha.-D-glucose or
acetobromo-.alpha.-D-galactose in the presence of a base such as
silver carbonate, sodium hydride or the like in an inert solvent.
As the inert solvent used in the reaction, for example,
tetrahydrofuran, dimethoxyethane, N,N-dimethylformamide, a mixed
solvent thereof and the like can be illustrated. The reaction
temperature is usually from room temperature to reflux temperature,
and the reaction time is usually from 1 hour to 1 day, varying
based on a used starting material, solvent and reaction
temperature. [2] In case that one of Q.sup.3 and T.sup.3 is a
halo(C.sub.1-6 alkyl) group in a benzylpyrazole derivative
represented by the above general formula (III), a corresponding
compound represented by the above general formula (II) of the
present invention can be prepared by subjecting a corresponding
benzylpyrazole derivative represented by the above general formula
(III) to glycosidation using acetobromo-.alpha.-D-glucose or
acetobromo-.alpha.-D-galactose in the presence of a base such as
potassium carbonate or the like in an inert solvent. As the inert
solvent used in the reaction, for example, tetrahydrofuran,
acetonitrile, a mixed solvent thereof and the like can be
illustrated. The reaction temperature is usually from room
temperature to reflux temperature, and the reaction time is usually
from 1 hour to 1 day, varying based on a used starting material,
solvent and reaction temperature. [3] In case that one of Q.sup.3
and T.sup.3 is a C.sub.2-6 alkyl group, a C.sub.1-6
alkoxy-substituted (C.sub.1-6 alkyl) group or a C.sub.3-7
cycloalkyl group in a benzylpyrazole derivative represented by the
above general formula (III), a corresponding compound represented
by the above general formula (II) of the present invention can be
also prepared by subjecting a corresponding benzylpyrazole
derivative represented by the above general formula (III) to
glycosidation using acetobromo-.alpha.-D-glucose or
acetobromo-.alpha.-D-galactose in the presence of a base such as
sodium hydroxide, potassium hydroxide, potassium carbonate or the
like and a phase transfer catalyst such as
benzyltri(n-butyl)ammonium chloride, benzyltri(n-butyl)ammonium
bromide, tetra(n-butyl)ammonium hydrogen sulfate or the like in an
inert solvent containing water. As the inert solvent used in the
reaction, dichloromethane, toluene, benzotrifluoride, a mixed
solvent thereof and the like can be illustrated. The reaction
temperature is usually from 0.degree. C. to reflux temperature, and
the reaction time is usually from 30 minutes to 1 day, varying
based on a used starting material, solvent and reaction
temperature.
The obtained glycosidated benzylpyrazole derivative represented by
the above general formula (II) can be also used in the subsequent
process after suitably converting into a salt thereof and
separating in the usual way.
Process 1-9
A pyrazole derivative represented by the above general formula (I)
of the present invention can be prepared by subjecting a compound
represented by the above general formula (II) to alkaline
hydrolysis, and removing a protective group or subjecting a nitro
group of the resulting compound to reduction as occasion demands.
As the solvent used in the hydrolysis reaction, for example,
methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof
and the like can be illustrated. As the base, for example, sodium
hydroxide, sodium methoxide, sodium ethoxide and the like can be
illustrated. The reaction temperature is usually from 0.degree. C.
to reflux temperature, and the reaction time is usually from 30
minutes to 1 day, varying based on a used starting material,
solvent and reaction temperature. As mentioned above, in case of
compounds having a protective group in R.sup.11, R.sup.12, R.sup.14
and/or R.sup.15 after the hydrolysis, the protective group can be
suitably removed in the usual way. Furthermore, after the
completion of the above reaction, compounds having a nitro group in
R.sup.2 represented by the above general formula (I) can be also
derived into a corresponding compound having an amino group by
catalytic reduction using a platinum catalyst such as platinum
oxide in an inert solvent such as ethyl acetate at usually room
temperature to reflux temperature for usually 30 minutes to 1 day
in the usual way.
Among the compounds represented by the above general formula (III)
as starting materials, there can be the following three tautomers
in compounds wherein R.sup.11 is a hydrogen atom, varying based on
difference in the reaction conditions, and the compounds
represented by the above general formula (III) include all the
compounds:
##STR00022## wherein R, R.sup.3, R.sup.6, R.sup.7, R.sup.12,
R.sup.14, R.sup.15, X, Y and Z have the same meanings as defined
above.
Of the compounds represented by the above general formula (I) of
the present invention, a compound wherein R.sup.1 represents a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
hydroxy(C.sub.2-6 alkyl) group, a C.sub.3-7 cycloalkyl group, a
C.sub.3-7 cycloalkyl-substituted (C.sub.1-6 alkyl) group or an
aryl-substituted (C.sub.1-6 alkyl) group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group, an amino group, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group, for example, can be prepared
according to the following procedure:
##STR00023## wherein L.sup.3 represents a leaving group such as a
halogen atom, a mesyloxy group, a tosyloxy group or the like;
R.sup.21 represents a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a hydroxy(C.sub.2-6 alkyl) group which may have a protective
group, a C.sub.3-7 cycloalkyl group, a C.sub.3-7
cycloalkyl-substituted (C.sub.1-6 alkyl) group or an
aryl-substituted (C.sub.1-6 alkyl) group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group which may have a protective group,
an amino group which may have a protective group, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group; R.sup.31 represents a C.sub.1-6
alkyl group, a C.sub.2-6 alkenyl group, a hydroxy(C.sub.2-6 alkyl)
group, a C.sub.3-7 cycloalkyl group, a C.sub.3-7
cycloalkyl-substituted (C.sub.1-6 alkyl) group or an
aryl-substituted (C.sub.1-6 alkyl) group which may have the same or
different 1 to 3 substituents selected from the group consisting of
a halogen atom, a hydroxy group, an amino group, a C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group; and R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.12, R.sup.14, R.sup.15, Q,
Q.sup.2, T, T.sup.2, X, Y and Z have the same meanings as defined
above. Process 2
A pyrazole derivative represented by the above general formula (Ia)
of the present invention can be prepared by subjecting a compound
represented by the above general formula (IIa) to hydrolysis
according to a similar method to that described in the above
process 1-9 and N-alkylation using an N-alkylating agent
represented by the above general formula (XV) in the presence of a
base such as cesium carbonate or potassium carbonate in an inert
solvent, and in case of compounds having a protective group,
suitably removing the protective group in the usual way as occasion
demands. As the inert solvent used in the N-alkylation, for
example, acetonitrile, ethanol, 1,2-dimethoxyethane,
tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, a mixed
solvent thereof and the like can be illustrated. The reaction
temperature is usually from room temperature to reflux temperature,
and the reaction time is usually from 10 minutes to 1 day, varying
based on a used starting material, solvent and reaction
temperature.
Of the compounds represented by the above general formula (I) of
the present invention, a compound wherein R.sup.1 represents a
hydrogen atom, for example, can be also prepared according to the
following procedure:
##STR00024## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.12, R.sup.14, R.sup.15, Q, Q.sup.2, T, T.sup.2, X, Y
and Z have the same meanings as defined above. Process 3-1
A compound represented by the above general formula (XVII) can be
prepared by subjecting a compound represented by the above general
formula (XVI) to catalytic hydrogenation using a palladium catalyst
such as palladium-carbon powder in an inert solvent to remove the
benzyl group. As the solvent used in the catalytic hydrogenation,
for example, methanol, ethanol, tetrahydrofuran, ethyl acetate, a
mixed solvent thereof and the like can be illustrated. The reaction
temperature is usually from 0.degree. C. to reflux temperature, and
the reaction time is usually from 1 hour to 2 days, varying based
on a used starting material, solvent and reaction temperature.
Process 3-2
A compound represented by the above general formula (IIa) of the
present invention can be prepared by condensing a compound
represented by the above general formula (XVII) with an amine
derivative represented by the above general formula (XVIII) in the
presence of a condensing agent such as
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or
dicyclohexylcarbodiimide and in the presence or absence of a base
such as triethylamine or N,N-diisopropylethylamine in an inert
solvent after suitably adding 1-hydroxybenzotriazole as occasion
demands. As the solvent used in the condensing reaction, for
example, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, a
mixed solvent thereof and the like can be illustrated. The reaction
temperature is usually from 0.degree. C. to reflux temperature, and
the reaction time is usually from 1 hour to 2 days, varying based
on a used starting material, solvent and reaction temperature.
Process 3-3
A pyrazole derivative represented by the above general formula (Ib)
of the present invention can be prepared by subjecting a compound
represented by the above general formula (IIa) to alkaline
hydrolysis, and removing the protective group in the usual way as
occasion demands. As the solvent used in the hydrolysis reaction,
for example, methanol, ethanol, tetrahydrofuran, water, a mixed
solvent thereof and the like can be illustrated. As the base, for
example, sodium hydroxide, sodium methoxide, sodium ethoxide and
the like can be illustrated. The reaction temperature is usually
from 0.degree. C. to reflux temperature, and the reaction time is
usually from 30 minutes to 1 day, varying based on a used starting
material, solvent and reaction temperature. In case of compounds
having a protective group in R.sup.12, R.sup.14 and/or R.sup.15
after the hydrolysis, the protective group can be suitably removed
in the usual way as the process 1-9.
Of the compounds represented by the above general formula (I) of
the present invention, a compound wherein R.sup.1 represents a
hydrogen atom; X represents a single bond; and Y represents a
C.sub.2-6 alkylene group or a C.sub.2-6 alkenylene group, for
example, can be prepared according to the following procedures:
##STR00025## wherein L.sup.4 represents a leaving group such as a
chlorine atom, a bromine atom, an iodine atom, a
trifluoromethanesulfonyloxy group or the like; Y.sup.1 represents a
single bond or a C.sub.1-4 alkylene group; and R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.12, R.sup.14, R.sup.15,
Q, Q.sup.2, T, T.sup.2 and Z have the same meanings as defined
above. Process 4-1
A pyrazole derivative represented by the above general formula
(XXI) can be prepared by subjecting a pyrazole derivative
represented by the above general formula (XIX) to Heck reaction
with an olefine derivative represented by the above general formula
(XX) using a palladium catalyst such as palladium-carbon powder,
palladium acetate, tetrakis(triphenylphosphine)palladium,
dibenzylideneacetonepalladium or bis(triphenylphosphine)palladium
dichloride in the presence or absence of a phosphine ligand such as
tris(2-methylphenyl)phosphine or triphenylphosphine and in the
presence of a base such as triethylamine, sodium tert-butoxide,
potassium tert-butoxide or cesium fluoride in an inert solvent. As
the solvent used in the reaction, for example, acetonitrile,
toluene, tetrahydrofuran, a mixed solvent thereof and the like can
be illustrated. The reaction temperature is usually from 0.degree.
C. to reflux temperature, and the reaction time is usually from 1
hour to 2 days, varying based on a used starting material, solvent
and reaction temperature.
Process 4-2
A compound represented by the above general formula (XXII) can be
prepared by subjecting a compound represented by the above general
formula (XXI) to catalytic hydrogenation using a palladium catalyst
such as palladium-carbon powder in an inert solvent. As the solvent
used in the catalytic hydrogenation, for example, methanol,
ethanol, tetrahydrofuran, ethyl acetate, a mixed solvent thereof
and the like can be illustrated. The reaction temperature is
usually from 0.degree. C. to reflux temperature, and the reaction
time is usually from 1 hour to 2 days, varying based on a used
starting material, solvent and reaction temperature.
Process 4-3
A compound represented by the above general formula (IIb) of the
present invention can be prepared by condensing a compound
represented by the above general formula (XXII) with an amine
derivative represented by the above general formula (XVIII) in the
presence of a condensing agent such as
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or
dicyclohexylcarbodiimideandabase such as triethylamineor
N,N-diisopropylethylamine in an inert solvent after suitably adding
1-hydroxybenzotriazole as occasion demands, and suitably removing
the protective group in the usual way as occasion demands. As the
solvent used in the condensing reaction, for example,
N,N-dimethylformamide, dichloromethane, tetrahydrofuran, a mixed
solvent thereof and the like can be illustrated. The reaction
temperature is usually from 0.degree. C. to reflux temperature, and
the reaction time is usually from 1 hour to 2 days, varying based
on a used starting material, solvent and reaction temperature.
Process 4-4
A pyrazole derivative represented by the above general formula (Ic)
of the present invention can be prepared by subjecting a compound
represented by the above general formula (IIb) to alkaline
hydrolysis, and suitably removing the protective group in the usual
way as occasion demands. As the solvent used in the hydrolysis
reaction, for example, methanol, ethanol, tetrahydrofuran, water, a
mixed solvent thereof and the like can be illustrated. As the base,
for example, sodium hydroxide, sodium methoxide, sodium ethoxide
and the like can be illustrated. The reaction temperature is
usually from 0.degree. C. to reflux temperature, and the reaction
time is usually from 30 minutes to 1 day, varying based on a used
starting material, solvent and reaction temperature. In case of
compounds having a protective group in R.sup.12, R.sup.14 and/or
R.sup.15 after the hydrolysis, the protective group can be suitably
removed in the usual way as the process 1-9.
##STR00026## In the formula, L.sup.4, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.12, R.sup.14, R.sup.15, Q,
Q.sup.2, T, T.sup.2, Y.sup.1 and Z have the same meanings as
defined above. Process 5-1
A compound represented by the above general formula (IIc) of the
present invention can be prepared by condensing a compound
represented by the above general formula (XXI) with an amine
derivative represented by the above general formula (XVIII) in the
presence of a condensing agent such as
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or
dicyclohexylcarbodiimide and a base such as triethylamine or
N,N-diisopropylethylamine in an inert solvent after suitably adding
1-hydroxybenzotriazole as occasion demands, and suitably removing
the protective group in the usual way as occasion demands. As the
solvent used in the condensing reaction, for example,
N,N-dimethylformamide, dichloromethane, tetrahydrofuran, a mixed
solvent thereof and the like can be illustrated. The reaction
temperature is usually from 0.degree. C. to reflux temperature, and
the reaction time is usually from 1 hour to 2 days, varying based
on a used starting material, solvent and reaction temperature.
Process 5-2
A pyrazole derivative represented by the above general formula
(IIc) of the present invention can be prepared by subjecting a
pyrazole derivative represented by the above general formula (XIX)
to Heck reaction with an olefine derivative represented by the
above general formula (XXIII) using a palladium catalyst such as
palladium-carbon powder, palladium acetate,
tetrakis(triphenylphosphine)palladium,
dibenzylideneacetonepalladium or bis(triphenylphosphine)palladium
dichloride in the presence or absence of a phosphine ligand such as
tris(2-methylphenyl)phosphine or triphenylphosphine and in the
presence of a base such as triethylamine, sodium tert-butoxide,
potassium tert-butoxide or cesium fluoride in an inert solvent. As
the solvent used in the reaction, for example, acetonitrile,
toluene, tetrahydrofuran, a mixed solvent thereof and the like can
be illustrated. The reaction temperature is usually from 0.degree.
C. to reflux temperature, and the reaction time is usually from 1
hour to 2 days, varying based on a used starting material, solvent
and reaction temperature.
Process 5-3
A pyrazole derivative represented by the above general formula (Id)
of the present invention can be prepared by subjecting a compound
represented by the above general formula (IIc) to alkaline
hydrolysis, and suitably removing the protective group in the usual
way as occasion demands. As the solvent used in the hydrolysis
reaction, for example, methanol, ethanol, tetrahydrofuran, water, a
mixed solvent thereof and the like can be illustrated. As the base,
for example, sodium hydroxide, sodium methoxide, sodium ethoxide
and the like can be illustrated. The reaction temperature is
usually from 0.degree. C. to reflux temperature, and the reaction
time is usually from 30 minutes to 1 day, varying based on a used
starting material, solvent and reaction temperature. In case of
compounds having a protective group in R.sup.12, R.sup.14 and/or
R.sup.15 after the hydrolysis, the protective group can be suitably
removed in the usual way as the process 1-9.
Process 5-4
A compound represented by the above general formula (IIb) can be
prepared by subjecting a compound represented by the above general
formula (IIc) to catalytic hydrogenation using a palladium catalyst
such as palladium-carbon powder in an inert solvent. As the solvent
used in the catalytic hydrogenation, for example, methanol,
ethanol, tetrahydrofuran, ethyl acetate, a mixed solvent thereof
and the like can be illustrated. The reaction temperature is
usually from 0.degree. C. to reflux temperature, and the reaction
time is usually from 1 hour to 2 days, varying based on a used
starting material, solvent and reaction temperature.
Process 5-5
A compound represented by the above general formula (Ic) of the
present invention can be prepared by subjecting a compound
represented by the above general formula (Id) to catalytic
hydrogenation using a palladium catalyst such as palladium-carbon
powder in an inert solvent. As the solvent used in the catalytic
hydrogenation, for example, methanol, ethanol, tetrahydrofuran,
ethyl acetate, a mixed solvent thereof and the like can be
illustrated. The reaction temperature is usually from 0.degree. C.
to reflux temperature, and the reaction time is usually from 1 hour
to 2 days, varying based on a used starting material, solvent and
reaction temperature.
Process 5-6
A pyrazole derivative represented by the above general formula (Ic)
of the present invention can be prepared by subjecting a compound
represented by the above general formula (IIb) to alkaline
hydrolysis, and suitably removing the protective group in the usual
way as occasion demands. As the solvent used in the hydrolysis
reaction, for example, methanol, ethanol, tetrahydrofuran, water, a
mixed solvent thereof and the like can be illustrated. As the base,
for example, sodium hydroxide, sodium methoxide, sodium ethoxide
and the like can be illustrated. The reaction temperature is
usually from 0.degree. C. to reflux temperature, and the reaction
time is usually from 30 minutes to 1 day, varying based on a used
starting material, solvent and reaction temperature. In case of
compounds having a protective group in R.sup.12, R.sup.14 and/or
R.sup.15 after the hydrolysis, the protective group can be suitably
removed in the usual way as the process 1-9.
The compounds represented by the above general formula (I) of the
present invention obtained by the above production processes can be
isolated and purified by conventional separation means such as
fractional recrystallization, purification using chromatography,
solvent extraction and solid phase extraction.
The pyrazole derivatives represented by the above general formula
(I) of the present invention can be converted into their
pharmaceutically acceptable salts in the usual way. Examples of
such salts include acid addition salts with mineral acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, nitric acid, phosphoric acid and the like, acid addition
salts with organic acids such as formic acid, acetic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
propionic acid, citric acid, succinic acid, tartaric acid, fumaric
acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic
acid, malic acid, carbonic acid, glutamic acid, aspartic acid and
the like, salts with inorganic bases such as a sodium salt, a
potassium salt and the like, and salts with organic bases such as
N-methyl-D-glucamine, N,N'-dibenzyletylenediamine, 2-aminoethanol,
tris(hydroxymethyl)aminomethane, arginine, lysine and the like.
The compounds represented by the above general formula (I) of the
present invention include their solvates with pharmaceutically
acceptable solvents such as ethanol and water.
Of the pyrazole derivatives represented by the above general
formula (I) of the present invention and the prodrugs thereof,
there are two geometrical isomers in each compound having an
unsaturated bond. In the present invention, either of cis(Z)-isomer
or trans(E)-isomer can be employed.
Of the pyrazole derivatives represented by the above general
formula (I) of the present invention and the prodrugs thereof,
there are two optical isomers, R-isomer and S-isomer, in each
compound having an asymmetric carbon atom excluding the
glucopyranosyloxy moiety or the galactopyranosyloxy moiety. In the
present invention, either of the isomers can be employed, and a
mixture of both isomers can be also employed.
A prodrug of a compound represented by the above general formula
(I) of the present invention can be prepared by introducing an
appropriate group forming a prodrug into any one or more groups
selected from a hydroxy group in the glucopyranosyl moiety or the
galactopyranosyl moiety, or optionally in R.sup.1, R.sup.2R.sup.4
or R.sup.5, a cyclic amino group in case that R.sup.1 is a hydrogen
atom, and an amino group in case that R.sup.1, R.sup.2, R.sup.4 or
R.sup.5 is a substituent having an amino group of the compound
represented by the above general formula (I) using a corresponding
reagent to produce a prodrug such as a halide compound or the like
in the usual way, and then by suitably isolating and purificating
in the usual way as occasion demands. As a group forming a prodrug
used in a hydroxy group or an amino group, for example, a C.sub.2-7
acyl group, a C.sub.1-6 alkoxy-substituted (C.sub.2-7 acyl) group,
a C.sub.2-7 alkoxycarbonyl-substituted (C.sub.2-7 acyl) group, a
C.sub.2-7 alkoxycarbonyl group, an aryl-substituted (C.sub.2-7
alkoxycarbonyl) group, a C.sub.1-6 alkoxy-substituted (C.sub.2-7
alkoxycarbonyl) group or the like can be illustrated. As a group
forming a prodrug used in a cyclic amino group, for example, a
C.sub.2-7 acyl group, a C.sub.1-6 alkoxy-substituted (C.sub.2-7
acyl) group, a C.sub.2-7 alkoxycarbonyl-substituted (C.sub.2-7
acyl) group, a C.sub.2-7 alkoxycarbonyl group, a C.sub.1-6
alkoxy-substituted (C.sub.2-7 alkoxycarbonyl) group, a (C.sub.2-7
acyloxy)methyl group, a 1-(C.sub.2-7 acyloxy)ethyl group, a
(C.sub.2-7 alkoxycarbonyl)oxymethyl group, a 1-[(C.sub.2-7
alkoxycarbonyl)oxy]ethyl group, a (C.sub.3-7
cycloalkyl)oxycarbonyloxymethyl group, a 1-[(C.sub.3-7
cycloalkyl)oxycarbonyloxy]ethyl group or the like can be
illustrated. The term "C.sub.2-7 acyl group" means a
straight-chained or branched acyl group having 2 to 7 carbon atoms
such as an acetyl group, a propionyl group, a butyryl group, an
isobutyryl group, a valeryl group, a pivaloyl group, a hexanoyl
group or the like; and the term "C.sub.1-6 alkoxy-substituted
(C.sub.2-7 acyl) group" means the above C.sub.2-7 acyl group
substituted by the above C.sub.1-6 alkoxy group; the term
"C.sub.2-7 alkoxycarbonyl-substituted (C.sub.2-7 acyl) group" means
the above C.sub.2-7 acyl group substituted by the above C.sub.2-7
alkoxycarbonyl group; the term "aryl-substituted (C.sub.2-7
alkoxycarbonyl) group" means the above C.sub.2-7 alkoxycarbonyl
group substituted by the above aryl group, such as a
benzyloxycarbonyl group; the term "C.sub.1-6 alkoxy-substituted
(C.sub.2-7 alkoxycarbonyl) group" means the above C.sub.2-7
alkoxycarbonyl group substituted by the above C.sub.1-6 alkoxy
group; the term "(C.sub.2-7 acyloxy)methyl group" means a
hydroxymethyl group O-substituted by the above C.sub.2-7 acyl
group; the term "1-(C.sub.2-7 acyloxy)ethyl group" means a
1-hydroxyethyl group O-substituted by the above C.sub.2-7 acyl
group; the term "(C.sub.2-7 alkoxycarbonyl)oxymethyl group" means a
hydroxymethyl group substituted by the above C.sub.2-7
alkoxycarbonyl group; and the term "1-[(C.sub.2-7
alkoxycarbonyl)oxy]ethyl group" means a 1-hydroxyethyl group
O-substituted by the above C.sub.2-7 alkoxycarbonyl group. In
addition, the term "(C.sub.3-7 cycloalkyl)oxycarbonyl group" means
a cyclic alkoxycarbonyl group having the above C.sub.3-7 cycloalkyl
group; the term "(C.sub.3-7 cycloalkyl)oxycarbonyloxymethyl group"
means a hydroxymethyl group O-substituted by the above (C.sub.3-7
cycloalkyl)oxycarbonyl group; and the term "1-[(C.sub.3-7
cycloalkyl)oxycarbonyloxy]ethyl group" means a 1-hydroxyethyl group
O-substituted by the above (C.sub.3-7 cycloalkyl)oxycarbonyl group.
Furthermore, as a group forming a prodrug, a glucopyranosyl group
or a galactopyranosyl group can be illustrated. For example, these
groups are preferably introduced into the hydroxy group at the 4 or
6 position of the glucopyranosyl group or the galactopyranosyl
group, and are more preferably introduced into the hydroxy group at
the 4 or 6 position of the glucopyranosyl group.
The pyrazole derivatives represented by the above general formula
(I) of the present invention, for example, showed a potent
inhibitory activity in human SGLT1 in a human SGLT1 inhibitory
activity confirmatory test as described below, and exerted an
excellent inhibitory activity of blood glucose level increase in a
confirmatory test of the inhibitory activity of blood glucose level
increase in rat. Thus, the pyrazole derivatives represented by the
above general formula (I) of the present invention exhibit an
excellent SGLT1 inhibitory activity at the small intestine, and can
remarkably inhibit blood glucose level increase and/or decrease
blood galactose level by inhibiting or delaying glucose and
galactose absorption. Therefore, a pharmaceutical composition
comprising as an active ingredient a pyrazole derivative
represented by the above general formula (I) of the present
invention, a pharmaceutically acceptable salt and a prodrug thereof
is extremely useful as an agent for inhibiting postprandial
hypreglycemia, an agent for the inhibition of advancing impaired
glucose tolerance (IGT) or impaired fasting glycemia (IFG) into
diabetes in a subject, and an agent for the prevention or treatment
of a disease associated with hyperglycemia such as diabetes,
impaired glucose tolerance, impaired fasting glycemia, diabetic
complications (e.g., retinopathy, neuropathy, nephropathy, ulcer,
macroangiopathy), obesity, hyperinsulinemia, hyperlipidemia,
hypercholesterolemia, hypertriglyceridemia, lipid metabolism
disorder, atherosclerosis, hypertension, congestive heart failure,
edema, hyperuricemia, gout or the like, which relates to SGLT1
activity at the small intestine, and an agent for the prevention or
treatment of a disease associated with increasing blood galactose
level such as galactosemia.
Furthermore, the compounds of the present invention can be suitably
used in combination with at least one member selected from drugs
other than SGLT2 inhibitors. Examples of the drugs which can be
used in combination with the compounds of the present invention
include an insulin sensitivity enhancer, a glucose absorption
inhibitor, a biguanide, an insulin secretion enhancer, a SGLT2
inhibitor, an insulin or insulin analogue, a glucagon receptor
antagonist, an insulin receptor kinase stimulant, a tripeptidyl
peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a
protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase
inhibitor, a glucose-6-phosphatase inhibitor, a
fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase
inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a
glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a
glucagon-like peptide-1 analogue, a glucagon-like peptide-1
agonist, amylin, an amylin analogue, an amylin agonist, an aldose
reductase inhibitor, an advanced glycation endproducts formation
inhibitor, a protein kinase C inhibitor, a .gamma.-aminobutyric
acid receptor antagonist, a sodium channel antagonist, a transcript
factor NF-.kappa.B inhibitor, a lipid peroxidase inhibitor, an
N-acetylated-.alpha.-linked-acid-dipeptidase inhibitor,
insulin-like growth factor-I, platelet-derived growth factor
(PDGF), a platelet-derived growth factor (PDGF) analogue (e.g.,
PDGF-AA, PDGF-BB, PDGF-AB), epidermal growth factor (EGF), nerve
growth factor, a carnitine derivative, uridine,
5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide,
Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme
A reductase inhibitor, a fibric acid derivative, a
.beta..sub.3-adrenoceptor agonist, an acyl-coenzyme A cholesterol
acyltransferase inhibitor, probcol, a thyroid hormone receptor
agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a
microsomal triglyceride transfer protein inhibitor, a lipoxygenase
inhibitor, a carnitine palmitoyltransferase inhibitor, a squalene
synthase inhibitor, a low-density lipoprotein receptor enhancer, a
nicotinic acid derivative, a bile acid sequestrant, a sodium/bile
acid cotransporter inhibitor, a cholesterol ester transfer protein
inhibitor, an appetite suppressant, an angiotensin-converting
enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin
II receptor antagonist, an endothelin-converting enzyme inhibitor,
an endothelin receptor antagonist, a diuretic agent, a calcium
antagonist, a vasodilating antihypertensive agent, a sympathetic
blocking agent, a centrally acting antihypertensive agent, an
.alpha..sub.2-adrenoceptor agonist, an antiplatelets agent, a uric
acid synthesis inhibitor, a uricosuric agent and a urinary
alkalinizer.
In case of uses of the compound of the present invention in
combination with the above one or more drugs, the present invention
includes either dosage forms of simultaneous administration as a
single preparation or separated praparations in way of the same or
different administration route, and administration at different
dosage intervals as separated praparations in way of the same or
different administration route. A pharmaceutical combination
comprising the compound of the present invention and the above
drug(s) includes both dosage forms as a single preparation and
separated preparations for combination as mentioned above.
The compounds of the present invention can obtain more advantageous
effects than additive effects in the prevention or treatment of the
above diseases when using suitably in combination with the above
one or more drugs. Also, the administration dose can be decreased
in comparison with administration of either drug alone, or adverse
effects of coadministrated drugs other than SGLT1 inhibitors can be
avoided or declined.
Concrete compounds as the drugs used for combination and preferable
diseases to be treated are exemplified as follows. However, the
present invention is not limited thereto, and the concrete
compounds include their free compounds, and their or other
pharmaceutically acceptable salts.
As insulin sensitivity enhancers, peroxisome proliferator-activated
receptor-.gamma. agonists such as troglitazone, pioglitazone
hydrochloride, rosiglitazone maleate, sodium darglitazone,
GI-262570, isaglitazone, LG-100641, NC-2100, T-174, DRF-2189,
CLX-0921, CS-011, GW-1929, ciglitazone, sodium englitazone and
NIP-221, peroxisome proliferator-activated receptor-.alpha.
agonists such as GW-9578 and BM-170744, peroxisome
proliferator-activated receptor-.alpha./.gamma. agonists such as
GW-409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158
and DRF-MDX8, retinoid X receptor agonists such as ALRT-268,
AGN-4204, MX-6054, AGN-194204, LG-100754 and bexarotene, and other
insulin sensitivity enhancers such as reglixane, ONO-5816, MBX-102,
CRE-1625, FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050,
HQL-975, CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242,
LY-510929, AR-H049020 and GW-501516 are illustrated. Insulin
sensitivity enhancers are used preferably for diabetes, impaired
glucose tolerance, diabetic complications, obesity,
hyperinsulinemia, hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, lipid metabolism disorder or atherosclerosis,
and more preferably for diabetes, impaired glucose tolerance or
hyperinsulinemia because of improving the disturbance of insulin
signal transduction in peripheral tissues and enhancing glucose
uptake into the tissues from the blood, leading to lowering of
blood glucose level.
As glucose absorption inhibitors, compounds other than SGLT1
inhibitors, for example, .alpha.-glucosidase inhibitors such as a
carbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25,637,
camiglibose and MDL-73,945, and .alpha.-amylase inhibitors such as
AZM-127 are illustrated. Glucose absorption inhibitors are used
preferably for diabetes, impaired glucose tolerance, diabetic
complications, obesity or hyperinsulinemia, and more preferably for
impaired glucose tolerance because of inhibiting the
gastrointestinal enzymatic digestion of carbohydrates contained in
foods, and inhibiting or delaying the absorption of glucose into
the body.
As biguanides, phenformin, buformin hydrochloride, metformin
hydrochloride or the like are illustrated. Biguanides are used
preferably for diabetes, impaired glucose tolerance, diabetic
complications or hyperinsulinemia, and more preferably for
diabetes, impaired glucose tolerance or hyperinsulinemia because of
lowering blood glucose level by inhibitory effects on hepatic
gluconeogenesis, accelerating effects on anaerobic glycolysis in
tissues or improving effects on insulin resistance in peripheral
tissues.
As insulin secretion enhancers, tolbutamide, chlorpropamide,
tolazamide, acetohexamide, glyclopyramide, glyburide
(glibenclamide), gliclazide, 1-butyl-3-metanilylurea, carbutamide,
glibornuride, glipizide, gliquidone, glisoxapide, glybuthiazol,
glybuzole, glyhexamide, sodium glymidine, glypinamide,
phenbutamide, tolcyclamide, glimepiride, nateglinide, mitiglinide
calcium hydrate, repaglinide or the like are illustrated. In
addition, the insulin secretion enhancers include glucokinase
activators such as RO-28-1675. Insulin secretion enhancers are used
preferably for diabetes, impaired glucose tolerance or diabetic
complications, and more preferably for diabetes or impaired glucose
tolerance because of lowering blood glucose level by acting on
pancreatic .beta.-cells and enhancing the insulin secretion.
As SGLT2 inhibitors, T-1095 and compounds described in Japanese
patent publications Nos. Hei10-237089 and 2001-288178, and
International Publications Nos. WO01/16147, WO01/27128, WO01/68660,
WO01/74834, WO01/74835, WO02/28872, WO02/36602, WO02/44192,
WO02/53573 etc. are illustrated. SGLT2 inhibitors are used
preferably for diabetes, impaired glucose tolerance, diabetic
complications, obesity or hyperinsulinemia, and more preferably for
diabetes, impaired glucose tolerance, obesity or hyperinsulinemia
because of lowering blood glucose level by inhibiting the
reabsorption of glucose at the kidney's proximal tubule.
As insulin or insulin analogues, human insulin, animal-derived
insulin, human or animal-derived insulin analogues or the like are
illustrated. These preparations are used preferably for diabetes,
impaired glucose tolerance or diabetic complications, and more
preferably for diabetes or impaired glucose tolerance.
As glucagon receptor antagonists, BAY-27-9955, NNC-92-1687 or the
like are illustrated; as insulin receptor kinase stimulants,
TER-17411, L-783281, KRX-613 or the like are illustrated; as
tripeptidyl peptidase II inhibitors, UCL-1397 or the like are
illustrated; as dipeptidyl peptidase IV inhibitors, NVP-DPP728A,
TSL-225, P-32/98 or the like are illustrated; as protein tyrosine
phosphatase 1B inhibitors, PTP-112, OC-86839, PNU-177496 or the
like are illustrated; as glycogen phosphorylase inhibitors,
NN-4201, CP-368296 or the like are illustrated; as
fructose-bisphosphatase inhibitors, R-132917 or the like are
illustrated; as pyruvate dehydrogenase inhibitors, AZD-7545 or the
like are illustrated; as hepatic gluconeogenesis inhibitors,
FR-225659 or the like are illustrated; as glucagon-like peptide-1
analogues, exendin-4, CJC-1131 or the like are illustrated; as
glucagon-like peptide 1 agonists; AZM-134, LY-315902 or the like
are illustrated; and as amylin, amylin analogues or amylin
agonists, pramlintide acetate or the like are illustrated. These
drugs, glucose-6-phosphatase inhibitors, D-chiroinsitol, glycogen
synthase kinase-3 inhibitors and glucagon-like peptide-1 are used
preferably for diabetes, impaired glucose tolerance, diabetic
complications or hyperinsulinemia, and more preferably for diabetes
or impaired glucose tolerance.
As aldose reductase inhibitors, ascorbyl gamolenate, tolrestat,
epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598,
fidarestat, sorbinil, ponalrestat, risarestat, zenarestat,
minalrestat, methosorbinil, AL-1567, imirestat, M-16209, TAT,
AD-5467, zopolrestat, AS-3201, NZ-314, SG-210, JTT-811,
lindolrestat or the like are illustrated. Aldose reductase
inhibitors are preferably used for diabetic complications because
of inhibiting aldose reductase and lowering excessive intracellular
accumulation of sorbitol in accelated polyol pathway which are in
continuous hyperglycemic condition in the tissues in diabetic
complications.
As advanced glycation endproducts formation inhibitors,
pyridoxamine, OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride
or the like are illustrated. Advanced glycation endproducts
formation inhibitors are preferably used for diabetic complications
because of inhibiting formation of advanced glycation endproducts
which are accelated in continuous hyperglycemic condition in
diabetes and declining of cellular damage.
As protein kinase C inhibitors, LY-333531, midostaurin or the like
are illustrated. Protein kinase C inhibitors are preferably used
for diabetic complications because of inhibiting of protein kinase
C activity which is accelated in continuous hyperglycemic condition
in diabetes.
As .gamma.-aminobutyric acid receptor antagonists, topiramate or
the like are illustrated; as sodium channel antagonists, mexiletine
hydrochloride, oxcarbazepine or the like are illustrated; as
transcript factor NF-.kappa.B inhibitors, dexlipotam or the like
are illustrated; as lipid peroxidase inhibitors, tirilazad mesylate
or the like are illustrated; as
N-acetylated-.alpha.-linked-acid-dipeptidase inhibitors, GPI-5693
or the like are illustrated; and as carnitine derivatives,
carnitine, levacecamine hydrochloride, levocarnitine chloride,
levocarnitine, ST-261 or the like are illustrated. These drugs,
insulin-like growth factor-I, platelet-derived growth factor,
platelet derived growth factor analogues, epidermal growth factor,
nerve growth factor, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,
bimoclomol, sulodexide and Y-128 are preferably used for diabetic
complications.
As antidiarrhoics or cathartics, polycarbophil calcium, albumin
tannate, bismuth subnitrate or the like are illustrated. These
drugs are preferably used for diarrhea, constipation or the like
accompanying diabetes or the like.
As hydroxymethylglutaryl coenzyme A reductase inhibitors, sodium
cerivastatin, sodium pravastatin, lovastatin, simvastatin, sodium
fluvastatin, atorvastatin calcium hydrate, SC-45355, SQ-33600,
CP-83101, BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678,
BAY-10-2987, calcium pitavastatin, calcium rosuvastatin,
colestolone, dalvastatin, acitemate, mevastatin, crilvastatin,
BMS-180431, BMY-21950, glenvastatin, carvastatin, BMY-22089,
bervastatin or the like are illustrated. Hydroxymethylglutaryl
coenzyme A reductase inhibitors are used preferably for
hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid
metabolism disorder or atherosclerosis, and more preferably for
hyperlipidemia, hypercholesterolemia or atherosclerosis because of
lowering blood cholesterol level by inhibiting
hydroxymethylglutaryl coenzyme A reductase.
As fibric acid derivatives, bezafibrate, beclobrate, binifibrate,
ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate,
clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate,
pirifibrate, ronifibrate, simfibrate, theofibrate, AHL-157 or the
like are illustrated. Fibric acid derivatives are used preferably
for hyperinsulinemia, hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, lipid metabolism disorder or atherosclerosis,
and more preferably for hyperlipidemia, hypertriglyceridemia or
atherosclerosis because of activating hepatic lipoprotein lipase
and enhancing fatty acid oxidation, leading to lowering of blood
triglyceride level.
As .beta..sub.3-adrenoceptor agonists, BRL-28410, SR-58611A,
ICI-198157, ZD-2079, BMS-194449, BRL-37344, CP-331679, CP-114271,
L-750355, BMS-187413, SR-59062A, BMS-210285, LY-377604, SWR-0342SA,
AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A,
CL-316243, AJ-9677, GW-427353, N-5984, GW-2696, YM178 or the like
are illustrated. .beta..sub.3-Adrenoceptor agonists are used
preferably for obesity, hyperinsulinemia, hyperlipidemia,
hypercholesterolemia, hypertriglyceridemia or lipid metabolism
disorder, and more preferably for obesity or hyperinsulinemia
because of stimulating .beta..sub.3-adrenoceptor in adipose tissue
and enhancing the fatty acid oxidation, leading to induction of
energy expenditure.
As acyl-coenzyme A cholesterol acyltransferase inhibitors, NTE-122,
MCC-147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676, P-06139,
CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115,
FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-C8-434,
avasimibe, CI-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546,
YM-17E, lecimibide, 447C88, YM-750, E-5324, KW-3033, HL-004,
eflucimibe or the like are illustrated. Acyl-coenzyme A cholesterol
acyltransferase inhibitors are used preferably for hyperlipidemia,
hypercholesterolemia, hypertriglyceridemia or lipid metabolism
disorder, and more preferably for hyperlipidemia or
hypercholesterolemia because of lowering blood cholesterol level by
inhibiting acyl-coenzyme A cholesterol acyltransferase.
As thyroid hormone receptor agonists, sodium liothyronine, sodium
levothyroxine, KB-2611 or the like are illustrated; as cholesterol
absorption inhibitors, ezetimibe, SCH-48461 or the like are
illustrated; as lipase inhibitors, orlistat, ATL-962, AZM-131,
RED-103004 or the like are illustrated; as carnitine
palmitoyltransferase inhibitors, etomoxir or the like are
illustrated; as squalene synthase inhibitors, SDZ-268-198,
BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856 or
the like are illustrated; as nicotinic acid derivatives, nicotinic
acid, nicotinamide, nicomol, niceritrol, acipimox, nicorandil or
the like are illustrated; as bile acid sequestrants, colestyramine,
colestilan, colesevelam hydrochloride, GT-102-279 or the like are
illustrated; as sodium/bile acid cotransporter inhibitors, 264W94,
S-8921, SD-5613 or the like are illustrated; and as cholesterol
ester transfer protein inhibitors, PNU-107368E, SC-795, JTT-705,
CP-529414 or the like are illustrated. These drugs, probcol,
microsomal trigylceride transfer protein inhibitors, lipoxygenase
inhibitors and low-density lipoprotein receptor enhancers are
preferably used for hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia or lipid metabolism disorder.
As appetite suppressants, monoamine reuptake inhibitors, serotonin
reuptake inhibitors, serotonin releasing stimulants, serotonin
agonists (especially 5HT.sub.2C-agonists), noradrenaline reuptake
inhibitors, noradrenaline releasing stimulants,
.alpha..sub.1-adrenoceptor agonists, .beta..sub.2-adrenoceptor
agonists, dopamine agonists, cannabinoid receptor antagonists,
.gamma.-aminobutyric acid receptor antagonists, H.sub.3-histamine
antagonists, L-histidine, leptin, leptin analogues, leptin receptor
agonists, melanocortin receptor agonists (especially, MC3-R
agonists, MC4-R agonists), .alpha.-melanocyte stimulating hormone,
cocaine-and amphetamine-regulated transcript, mahogany protein,
enterostatin agonists, calcitonin, calcitonin-gene-related peptide,
bombesin, cholecystokinin agonists (especially CCK-A agonists),
corticotropin-releasing hormone, corticotrophin-releasing hormone
analogues, corticotropin-releasing hormone agonists, urocortin,
somatostatin, somatostatin analogues, somatostatin receptor
agonists, pituitary adenylate cyclase-activatingpeptide,
brain-derived neurotrophic factor, ciliary neurotrophic factor,
thyrotropin-releasing hormone, neurotensin, sauvagine, neuropeptide
Y antagonists, opioid peptide antagonists, galanin antagonists,
melanin-concentrating hormone antagonists, agouti-related protein
inhibitors and orexin receptor antagonists are illustrated.
Concretely, as monoamine reuptake inhibitors, mazindol or the like
are illustrated; as serotonin reuptake inhibitors, dexfenfluramine
hydrochloride, fenfluramine, sibutramine hydrochloride, fluvoxamine
maleate, sertraline hydrochloride or the like are illustrated; as
serotonin agonists, inotriptan, (+)-norfenfluramine or the like are
illustrated; as noradrenaline reuptake inhibitors, bupropion,
GW-320659 or the like are illustrated; as noradrenaline releasing
stimulants, rolipram, YM-992 or the like are illustrated; as
.beta..sub.2-adrenoceptor agonists, amphetamine, dextroamphetamine,
phentermine, benzphetamine, methamphetamine, phendimetrazine,
phenmetrazine, diethylpropion, phenylpropanolamine, clobenzorex or
the like are illustrated; as dopamine agonists, ER-230, doprexin,
bromocriptine mesylate or the like are illustrated; as cannabinoid
receptor antagonists, rimonabant or the like are illustrated; as
.gamma.-aminobutyric acid receptor antagonists, topiramate or the
like are illustrated; as H.sub.3-histamine antagonists, GT-2394 or
the like are illustrated; as leptin, leptin analogues or leptin
receptor agonists, LY-355101 or the like are illustrated; as
cholecystokinin agonists (especially CCK-A agonists), SR-146131;
SSR-125180, BP-3.200, A-71623, FPL-15849, GI-248573, GW-7178,
GI-181771, GW-7854, A-71378 or the like are illustrated; and as
neuropeptide Y antagonists, SR-120819-A, PD-160170, NGD-95-1,
BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01, J-115814
or the like are illustrated. Appetite suppressants are used
preferably for diabetes, impaired glucose tolerance, diabetic
complications, obesity, hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, lipid metabolism disorder, atherosclerosis,
hypertension, congestive heart failure, edema, hyperuricemia or
gout, and more preferably for obesity because of stimulating or
inhibiting the activities of intracerebral monoamines or bioactive
peptides in central appetite regulatory system and suppressing the
appetite, leading to reduction of energy intake.
As angiotensin-converting enzyme inhibitors, captopril, enalapri
maleate, alacepril, delapril hydrochloride, ramipril, lisinopril,
imidapril hydrochloride, benazepril hydrochloride, ceronapril
monohydrate, cilazapril, sodium fosinopril, perindopril erbumine,
calcium moveltipril, quinapril hydrochloride, spirapril
hydrochloride, temocapril hydrochloride, trandolapril, calcium
zofenopril, moexipril hydrochloride, rentiaprilorthelike are
illustrated. Angiotensin-converting enzyme inhibitors are
preferably used for diabetic complications or hypertension.
As neutral endopeptidase inhibitors, omapatrilat, MDL-100240,
fasidotril, sampatrilat, GW-660511X, mixanpril, SA-7060, E-4030,
SLV-306, ecadotril or the like are illustrated. Neutral
endopeptidase inhibitors are preferably used for diabetic
complications or hypertension.
As angiotensin II receptor antagonists, candesartan cilexetil,
candesartan cilexetil/hydrochlorothiazide, potassium losartan,
eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174,
L-158809, EXP-3312, olmesartan, tasosartan, KT-3-671, GA-0113,
RU-64276, EMD-90423, BR-9701 or the like are illustrated.
Angiotensin II receptor antagonists are preferably used for
diabetic complications or hypertension.
As endothelin-converting enzyme inhibitors, CGS-31447, CGS-35066,
SM-19712 or the like are illustrated; as endothelin receptor
antagonists, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201,
SB-215355, PD-180988, sodium sitaxsentan, BMS-193884, darusentan,
TBC-3711, bosentan, sodium tezosentan, J-104132, YM-598, S-0139,
SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan,
BMS-207940 or the like are illustrated. These drugs are preferably
used for diabetic complications or hypertension, and more
preferably for hypertension.
As diuretic agents, chlorthalidone, metolazone, cyclopenthiazide,
trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,
benzylhydrochlorothiazide, penflutizide, methyclothiazide,
indapamide, tripamide, mefruside, azosemide, etacrynic acid,
torasemide, piretanide, furosemide, bumetanide, meticrane,
potassium canrenoate, spironolactone, triamterene, aminophylline,
cicletanine hydrochloride, LLU-.alpha., PNU-80873A, isosorbide,
D-mannitol, D-sorbitol, fructose, glycerin, acetazolamide,
methazolamide, FR-179544, OPC-31260, lixivaptan, conivaptan
hydrochloride or the like are illustrated. Diuretic drugs are
preferably used for diabetic complications, hypertension,
congestive heart failure or edema, and more preferably for
hypertension, congestive heart failure or edema because of reducing
blood pressure or improving edema by increasing urinary
excretion.
As calcium antagonists, aranidipine, efonidipine hydrochloride,
nicardipine hydrochloride, barnidipine hydrochloride, benidipine
hydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine,
nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine
besilate, pranidipine, lercanidipine hydrochloride, isradipine,
elgodipine, azelnidipine, lacidipine, vatanidipine hydrochloride,
lemildipine, diltiazem hydrochloride, clentiazem maleate, verapamil
hydrochloride, S-verapamil, fasudil hydrochloride, bepridil
hydrochloride, gallopamil hydrochloride or the like are
illustrated; as vasodilating antihypertensive agents, indapamide,
todralazine hydrochloride, hydralazine hydrochloride, cadralazine,
budralazine or the like are illustrated; as sympathetic blocking
agents, amosulalol hydrochloride, terazosin hydrochloride,
bunazosin hydrochloride, prazosin hydrochloride, doxazosin
mesylate, propranolol hydrochloride, atenolol, metoprolol tartrate,
carvedilol, nipradilol, celiprolol hydrochloride, nebivolol,
betaxolol hydrochloride, pindolol, tertatolol hydrochloride,
bevantolol hydrochloride, timolol maleate, carteolol hydrochloride,
bisoprolol hemifumarate, bopindolol malonate, nipradilol,
penbutolol sulfate, acebutolol hydrochloride, tilisolol
hydrochloride, nadolol, urapidil, indoramin or the like are
illustrated; as centrally acting antihypertensive agents, reserpine
or the like are illustrated; and as .alpha..sub.2-adrenoceptor
agonists, clonidine hydrochloride, methyldopa, CHF-1035, guanabenz
acetate, guanfacine hydrochloride, moxonidine, lofexidine,
talipexole hydrochloride or the like are illustrated. These drugs
are preferably used for hypertension.
As antiplatelets agents, ticlopidine hydrochloride, dipyridamole,
cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dilazep
dihydrochloride, trapidil, beraprost sodium, aspirin or the like
are illustrated. Antiplatelets agents are preferably used for
atherosclerosis or congestive heart failure.
As uric acid synthesis inhibitors, allopurinol, oxypurinol or the
like are illustrated; as uricosuric agents, benzbromarone,
probenecid or the like are illustrated; and as urinary
alkalinizers, sodium hydrogen carbonate, potassium citrate, sodium
citrate or the like are illustrated. These drugs are preferably
used for hyperuricemia or gout.
In case of uses in combination with drugs other than SGLT2
inhibitors, for example, in the use for diabetes, the combination
with at least one member of the group consisting of an insulin
sensitivity enhancer, a glucose absorption inhibitor, a biguanide,
an insulin secretion enhancer, a SGLT2 inhibitors, an insulin or
insulin analogue, a glucagon receptor antagonist, an insulin
receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, a
dipeptidyl peptidase IV inhibitor, a protein tyrosine
phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a
glucose-6-phosphatase inhibitor, a fructose-bisphosphatase
inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic
gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase
kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like
peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an
amylin analogue, an amylin agonist and an appetite suppressant is
preferable; the combination with at least one member of the group
consisting of an insulin sensitivity enhancer, a biguanide, an
insulin secretion enhancer, a SGLT2 inhibitors, an insulin or
insulin analogue, a glucagon receptor antagonist, an insulin
receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, a
dipeptidyl peptidase IV inhibitor, a protein tyrosine
phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a
glucose-6-phosphatase inhibitor, a fructose-bisphosphatase
inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic
gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase
kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like
peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an
amylin analogue and an amylin agonist is more preferable; and the
combination with at least one member of the group consisting of an
insulin sensitivity enhancer, a biguanide, an insulin secretion
enhancer, a SGLT2 inhibitor and an insulin or insulin analogue is
most preferable. Similarly, in the use for diabetic complications,
the combination with at least one member of the group consisting of
an insulin sensitivity enhancer, a glucose absorption inhibitor, a
biguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an
insulin or insulin analogue, a glucagon receptor antagonist, an
insulin receptor kinase stimulant, a tripeptidyl peptidase II
inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine
phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a
glucose-6-phosphatase inhibitor, a fructose-bisphosphatase
inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic
gluconeogenesis inhibitor, D-chiroinsitol, glycogen synthase
kinase-3 inhibitors, glucagon-like peptide-1, a glucagon-like
peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an
amylin analogue, an amylin agonist, an aldose reductase inhibitor,
an advanced glycation endproducts formation inhibitor, a protein
kinase C inhibitor, a .gamma.-aminobutyric acid antagonist, a
sodium channel antagonist, a transcript factor NF-.kappa.B
inhibitor, a lipid peroxidase inhibitor, an
N-acetylated-.alpha.-linked-acid-dipeptidase inhibitor,
insulin-like growth factor-I, platelet-derived growth factor, a
platelet derived growth factor analogue, epidermal growth factor,
nerve growth factor, a carnitine derivative, uridine,
5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide,
Y-128, an angiotensin-converting enzyme inhibitor, a neutral
endopeptidase inhibitor, an angiotensin II receptor antagonist, an
endothelin-converting enzyme inhibitor, an endothelin receptor
antagonist and a diuretic agnet is preferable; and the combination
with at least one member of the group consisting of an aldose
reductase inhibitor, an angiotensin-converting enzyme inhibitor, a
neutral endopeptidase inhibitor and an angiotensin II receptor
antagonist is more preferable. Furthermore, in the use for obesity,
the combination with at least one member of the group consisting of
an insulin sensitivity enhancer, a glucose absorption inhibitor, a
biguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an
insulin or insulin analogue, a glucagon receptor antagonist, an
insulin receptor kinase stimulant, a tripeptidyl peptidase II
inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine
phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a
glucose-6-phosphatase inhibitor, a fructose-bisphosphatase
inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic
gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase
kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like
peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an
amylin analogue, an amylin agonist, a .beta..sub.3-adrenoceptor
agonist and an appetite suppressant is preferable; and the
combination with at least one member of the group consisting of a
SGLT2 inhibitor, a .beta..sub.3-adrenoceptor agonist and an
appetite suppressant is more preferable.
When the pharmaceutical compositions of the present invention are
employed in the practical treatment, various dosage forms are used
depending on their uses. As examples of the dosage forms, powders,
granules, fine granules, dry sirups, tablets, capsules, injections,
solutions, ointments, suppositories, poultices and the like are
illustrated, which are orally or parentally administered. The
pharmaceutical compositions of the present invention also include
sustained release formulation including gastrointestinal
mucoadhesive formulation (e.g., International publications Nos.
WO99/10010, WO99/26606, and Japanese patent publication No.
2001-2567).
These pharmaceutical compositions can be prepared by admixing with
or by diluting and dissolving with an appropriate pharmaceutical
additive such as excipients, disintegrators, binders, lubricants,
diluents, buffers, isotonicities, antiseptics, moistening agents,
emulsifiers, dispersing agents, stabilizing agents, dissolving aids
and the like, and formulating the mixture in accordance with
conventional methods. In case of the uses of the compound of the
present invention in combination with the drug(s) other than SGLT1
inhibitors, they can be prepared by formulating each active
ingredient together or individually.
When the pharmaceutical compositions of the present invention are
employed in the practical treatment, the dosage of a compound
represented by the above general formula (I), a pharmaceutically
acceptable salt thereof or a prodrug thereof as the active
ingredient is appropriately decided depending on the age, sex, body
weight and degree of symptoms and treatment of each patient, which
is approximately within the range of from 0.1 to 1,000 mg per day
per adult human in the case of oral administration and
approximately within the range of from 0.01 to 300 mg per day per
adult human in the case of parenteral administration, and the daily
dose can be divided into one to several doses per day and
administered suitably. Also, in case of the uses of the compound of
the present invention in combination with the drug(s) other than
SGLT1 inhibitors, the dosage of the compound of the present
invention can be decreased, depending on the dosage of the drug(s)
other than SGLT1 inhibitors.
EXAMPLES
The present invention is further illustrated in more detail by way
of the following Reference Examples, Examples and Test Examples.
However, the present invention is not limited thereto.
Reference Example 1
2-Amino-2-methylpropionamide
To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid (1
g) in N,N-dimethylformamide (10 mL) were added
1-hydroxybenzotriazole (0.63 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.21
g), triethylamine (1.76 mL) and 28% aqueous ammonia solution (2
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was poured into water, and the resulting mixture
was extracted with ethyl acetate. The organic layer was washed with
0.5 mol/L hydrochloric acid, water, 1 mol/L aqueous sodium
hydroxide solution, water and brine successively, and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure to give 2-benzyloxycarbonylamino-2-methylpropionamide
(0.26 g). This material was dissolved in methanol (5 mL). To the
solution was added 10% palladium-carbon powder (30 mg), and the
mixture was stirred under a hydrogen atmosphere for 3 hours. The
insoluble material was removed by filtration, and the filtrate was
concentrated under reduced pressure to give the title compound
(0.11 g).
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.15 (6H, s), 1.9 (2H,
brs), 6.83 (1H, brs), 7.26 (1H, brs)
Reference Example 2
4-[(4-Bromophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one
To a suspension of sodium hydride (60%, 3.85 g) in tetrahydrofuran
(250 mL) was added ethyl 4-methyl-3-oxopentanoate (15.2 g), and the
mixture was stirred at 0.degree. C. for 10 minutes. To the reaction
mixture was added a solution of 4-bromobenzyl bromide (20 g) in
tetrahydrofuran (100 mL), and the mixture was stirred at room
temperature overnight. To the reaction mixture was added water, and
the resulting mixture was extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
removed under reduced pressure. To a solution of the residue in
toluene (10 mL) was added hydrazine monohydrate (8.01 g), and the
mixture was stirred at 100.degree. C. overnight. After cooling the
reaction mixture to room temperature, the solvent was removed under
reduced pressure. To the residue was added ethyl acetate (20 mL),
and the mixture was stirred at room temperature for 2 hours. The
precipitated crystals were collected by filtration. The collected
crystals were washed with water and n-hexane successively, and
dried at 40.degree. C. under reduced pressure to give the title
compound (11.5 g).
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.07 (6H, d, J=7.1 Hz),
2.75-2.9 (1H, m), 3.55 (2H, s), 7.05-7.15 (2H, m), 7.35-7.45 (2H,
m)
Reference Example 3
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromophenyl)me-
thyl]-5-isopropyl-1H-pyrazole
To a suspension of
4-[(4-bromophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one
(5.0 g) in dichloromethane (50 mL) were added
acetobromo-.alpha.-D-glucose (7.0 g), benzyltri(n-butyl)ammonium
chloride (5.3 g) and 5 mol/L aqueous sodium hydroxide solution (8.5
mL), and the mixture was stirred at room temperature overnight. The
organic layer was separated, and the solvent was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the
title compound (4.12 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.25 (6H, m), 1.86 (3H,
s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m),
3.58 (1H, d, J=16.2 Hz), 3.64 (1H, d, J=16.2 Hz), 3.8-3.95 (1H, m),
4.15 (1H, dd, J=12.4 Hz, 2.2 Hz), 4.32 (1H, dd, J=12.4 Hz, 3.9 Hz),
5.15-5.35 (3H, m), 5.53 (1H, d, J=7.5 Hz), 6.95-7.05 (2H, m),
7.3-7.4 (2H, m)
Reference Example 4
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbox-
yprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromophenyl)m-
ethyl]-5-isopropyl-1H-pyrazole (3.0 g) and 3-butenoic acid (1.0 g)
in acetonitrile (15 mL) were added triethylamine (2.4 g), palladium
acetate(II) (0.11 g) and tris(2-methylphenyl)phosphine (0.29 g),
and the mixture was refluxed overnight under shading the light. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluent: ethyl
acetate-dichloromethane/methanol=10/1) to give the title compound
(1.74 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.84 (3H,
s), 2.01 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.8-2.95 (1H, m),
3.2-3.3 (2H, m), 3.59 (1H, d, J=16.0 Hz), 3.66 (1H, d, J=16.0 Hz),
3.8-3.9 (1H, m), 4.18 (1H, dd, J=12.3 Hz, 1.8 Hz), 4.33 (1H, dd,
J=12.3 Hz, 3.8 Hz), 5.15-5.35 (3H, m), 5.4-5.5 (1H, m), 6.2-6.3
(1H, m), 6.4-6.5 (1H, m), 7.0-7.1 (2H, m), 7.2-7.3 (2H, m)
Reference Example 5
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbox-
yvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 4 using acrylic acid instead of
3-butenoic acid.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.19 (6H, d, J=7.3 Hz), 1.84
(3H, s), 2.01 (3H, s), 2.04 (3H, s), 2.05 (3H, s), 2.85-3.0 (1H,
m), 3.66 (1H, d, J=16.2 Hz), 3.73 (1H, d, J=16.2 Hz), 3.85-3.95
(1H, m), 4.2 (1H, dd, J=12.6 Hz, 2.2 Hz), 4.34 (1H, dd, J=12.6 Hz,
4.1 Hz), 5.15-5.35 (3H, m), 5.5 (1H, d, J=7.7 Hz), 6.4 (1H, d,
J=15.7 Hz), 7.15-7.2 (2H, m), 7.4-7.5 (2H, m), 7.71 (1H, d, J=15.7
Hz)
Example 1
4-({4-[3-(Carbamoylmethylcarbamoyl)propyl]phenyl}methyl)-3-(.beta.-D-gluco-
pyranosyloxy)-5-isopropyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.34 g) in
N,N-dimethylformamide (1 mL) were added glycinamide hydrochloride
(0.12 g), 1-hydroxybenzotriazole (0.09 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15
g) and triethylamine (0.27 g), and the mixture was stirred at room
temperature overnight. The insoluble material was removed by
filtration. To the filtrate was added 5 mol/L aqueous sodium
hydroxide solution (0.5 mL), and the mixture was stirred at room
temperature for 1 hour. The insoluble material was removed by
filtration, and the filtrate was purified by preparative reverse
phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5
.mu.m, 120 .ANG., 20.times.50 mm, flow rate 30 mL/minute linear
gradient, water/acetonitrile=90/10-10/90) to give
4-({4-[(1E)-3-(carbamoylmethylcarbamoyl)prop-1-enyl]phenyl}methyl)-3-(.be-
ta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.03 g). This
material was dissolved in methanol (1 mL). To the solution was
added 10% palladium-carbon powder (0.01 g), and the mixture was
stirred at room temperature under a hydrogen atmosphere for 3
hours. The insoluble material was removed by filtration, and the
solvent of the filtrate was removed under reduced pressure to give
the title compound (0.02 g).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.85-1.95
(2H, m), 2.25 (2H, t, J=7.6 Hz), 2.6 (2H, t, J=7.5 Hz), 2.85-2.95
(1H, m), 3.25-3.4 (4H, m), 3.6-3.9 (6H, m), 5.0-5.1 (1H, m),
7.0-7.15 (4H, m)
Example 2
4-{[4-(3-Carbamoylpropyl)phenyl]methyl}-3-(.beta.-D-glucopyranosyloxy)-5-i-
sopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using ammonium chloride instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.8-1.95
(2H, m), 2.19 (2H, t, J=7.6 Hz), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95
(1H, m), 3.3-3.45 (4H, m), 3.6-3.8 (3H, m), 3.8-3.9 (1H, m),
5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 3
4-({4-[3-(2-Carbamoylethylcarbamoyl)propyl]phenyl}methyl)-3-(.beta.-D-gluc-
opyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 3-aminopropionamide instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.8-1.95
(2H, m), 2.15 (2H, t, J=7.3 Hz), 2.4 (2H, t, J=6.7 Hz), 2.56 (2H,
t, J=7.5 Hz), 2.85-2.95 (1H, m), 3.25-3.45 (6H, m), 3.6-3.9 (4H,
m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 4
4-({4-[3-(2-Aminoethylcarbamoyl)propyl]phenyl}methyl)-3-(.beta.-D-glucopyr-
anosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using N-benzyloxycarbonyl-1,2-diaminoethane
hydrochloride instead of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.85-1.95
(2H, m), 2.19 (2H, t, J=7.6 Hz), 2.58 (2H, t, J=7.5 Hz), 2.8 (2H,
t, J=6.1 Hz), 2.85-2.95 (1H, m), 3.2-3.4 (6H, m), 3.6-3.9 (4H, m),
5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 5
4-({4-[3-(3-Aminopropylcarbamoyl)propyl]phenyl}methyl)-3-(.beta.-D-glucopy-
ranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using N-benzyloxycarbonyl-1,3-diaminopropane
hydrochloride instead of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.6-1.7 (2H,
m), 1.8-1.95 (2H, m), 2.17 (2H, t, J=7.7 Hz), 2.57 (2H, t, J=7.5
Hz), 2.68 (2H, t, J=7.1 Hz), 2.85-2.95 (1H, m), 3.22 (2H, t, J=6.7
Hz), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15
(4H, m)
Example 6
4-({4-[3-(4-Aminobutylcarbamoyl)propyl]phenyl}methyl)-3-(.beta.-D-glucopyr-
anosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using N-benzyloxycarbonyl-1,4-diaminobutane
hydrochloride instead of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.45-1.65
(4H, m), 1.8-1.95 (2H, m), 2.16 (2H, t, J=7.5 Hz), 2.57 (2H, t,
J=7.7 Hz), 2.83 (2H, t, J=7.0 Hz), 2.85-3.0 (1H, m), 3.17 (2H, t,
J=6.6 Hz), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m),
7.0-7.15 (4H, m)
Example 7
4-[(4-{3-[(S)-1-Carbamoyl-2-(4-hydroxyphenyl)ethylcarbamoyl]propyl}phenyl)-
methyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using L-tyrosine amide hydrochloride instead
of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.7-1.8 (2H,
m), 2.1-2.2 (2H, m), 2.44 (2H, t, J=7.5 Hz), 2.76 (1H, dd, J=13.9
Hz, 9.3 Hz), 2.85-2.95 (1H, m), 3.04 (1H, dd, J=13.9 Hz, 5.5 Hz),
3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 4.57 (1H, dd, J=9.3 Hz, 5.5
Hz), 5.0-5.1 (1H, m), 6.65-6.75 (2H, m), 6.95-7.15 (6H, m)
Example 8
4-{[4-(3-Benzylcarbamoylpropyl)phenyl]methyl}-3-(.beta.-D-glucopyranosylox-
y)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using benzylamine instead of glycinamide
hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.85-1.95
(2H, m), 2.22 (2H, t, J=7.5 Hz), 2.57 (2H, t, J=7.5 Hz), 2.8-2.95
(1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 4.33 (2H, s), 5.0-5.1
(1H, m), 7.0-7.15 (4H, m), 7.15-7.45 (5H, m)
Example 9
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-phenethylcarbamoylprop-
yl)phenyl]methyl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using phenethylamine instead of glycinamide
hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.75-1.9
(2H, m), 2.12 (2H, t, J=7.5 Hz), 2.51 (2H, t, J=7.7 Hz), 2.77 (2H,
t, J=7.5 Hz), 2.8-2.95 (1H, m), 3.25-3.45 (6H, m), 3.6-3.9 (4H, m),
5.0-5.15 (1H, m), 6.95-7.05 (2H, m), 7.05-7.3 (7H, m)
Example 10
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[3-(3-pyridylmethylcarbam-
oyl)propyl]phenyl}methyl)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 3-picolylamine instead of glycinamide
hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.85-1.95
(2H, m), 2.22 (2H, t, J=7.6 Hz), 2.56 (2H, t, J=7.6 Hz), 2.85-2.95
(1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 4.37 (2H, s), 5.0-5.1
(1H, m), 7.0-7.15 (4H, m), 7.35-7.45 (1H, m), 7.7-7.8 (1H, m),
8.4-8.45 (1H, m), 8.45-8.5 (1H, m)
Example 11
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[2-(2-pyridyl)ethylcar-
bamoyl]propyl}phenyl)methyl]-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 2-(2-aminoethyl)pyridine instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.75-1.9
(2H, m), 2.11 (2H, t, J=7.5 Hz), 2.51 (2H, t, J=7.6 Hz), 2.85-3.0
(3H, m), 3.25-3.45 (4H, m), 3.52 (2H, t, J=6.9 Hz), 3.6-3.9 (4H,
m), 5.0-5.1 (1H, m), 6.95-7.15 (4H, m), 7.2-7.35 (2H, m), 7.7-7.8
(1H, m), 8.4-8.5 (1H, m)
Example 12
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[2-(dimethylamino)ethy-
lcarbamoyl]propyl}phenyl)methyl]-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using N,N-dimethylethylenediamine instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.8-1.95
(2H, m), 2.17 (2H, t, J=7.6 Hz), 2.25 (6H, s), 2.42 (2H, t, J=6.9
Hz), 2.57 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m), 3.25-3.4 (6H, m),
3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 13
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[2-(morpholin-4-yl)eth-
ylcarbamoyl]propyl}phenyl)methyl]-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 4-(2-aminoethyl)morpholine instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.8-1.95
(2H, m), 2.17 (2H, t, J=7.6 Hz), 2.4-2.55 (6H, m), 2.58 (2H, t,
J=7.6 Hz), 2.85-2.95 (1H, m), 3.25-3.45 (6H, m), 3.6-3.9 (8H, m),
5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 14
3-(.beta.-D-Glucopyranosyloxy)-4-{[4-(3-{2-[bis(2-hydroxyethyl)amino]ethyl-
carbamoyl}propyl)phenyl]methyl}-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using N,N-bis(2-hydroxyethyl)ethylenediamine
instead of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.8-1.95
(2H, m), 2.18 (2H, t, J=7.5 Hz), 2.5-2.7 (8H, m), 2.85-2.95 (1H,
m), 3.25 (2H, t, J=6.4 Hz), 3.3-3.4 (4H, m), 3.5-3.9 (8H, m),
5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 15
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{3-[bis(2-hydroxyethyl-
)amino]propylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
N,N-bis(2-hydroxyethyl)-1,3-diaminopropane instead of glycinamide
hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.6-1.75
(2H, m), 1.8-1.95 (2H, m), 2.17 (2H, t, J=7.5 Hz), 2.5-2.75 (8H,
m), 2.8-2.95 (1H, m), 3.21 (2H, t, J=6.7 Hz), 3.25-3.45 (4H, m),
3.5-3.9 (8H, m), 5.0-5.15 (1H, m), 7.0-7.2 (4H, m)
Example 16
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[3-(dimethylamino)prop-
ylcarbamoyl]propyl}phenyl)methyl]-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using N,N-dimethyl-1,3-diaminopropane
instead of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.6-1.75
(2H, m), 1.8-1.95 (2H, m), 2.16 (2H, t, J=7.5 Hz), 2.22 (6H, s),
2.3-2.35 (2H, m), 2.57 (2H, t, J=7.6 Hz), 2.85-2.95 (1H, m), 3.17
(2H, t, J=6.9 Hz), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H,
m), 7.0-7.15 (4H, m)
Example 17
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[2-(imidazol-1-yl)ethylcarbamoyl]p-
ropyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 1-(2-aminoethyl)imidazole instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.8-2.0
(4H, m), 2.17 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.7 Hz), 2.85-2.95
(1H, m), 3.14 (2H, t, J=6.8 Hz), 3.3-3.45 (4H, m), 3.6-3.9 (4H, m),
4.03 (2H, t, J=7.0 Hz), 5.0-5.1 (1H, m), 6.9-7.0 (1H, m), 7.0-7.15
(5H, m), 7.6-7.7 (1H, m)
Example 18
3-(.beta.-D-Glucopyranosyloxy)-4-({4-[3-(2-hydroxyethyl)carbamoylpropyl]ph-
enyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 2-aminoethanol instead of glycinamide
hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.8-1.95
(2H, m), 2.18 (2H, t, J=7.5 Hz), 2.57 (2H, t, J=7.5 Hz), 2.85-2.95
(1H, m), 3.27 (2H, t, J=5.8 Hz), 3.3-3.5 (4H, m), 3.57 (2H, t,
J=5.9 Hz), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 19
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-(hydroxymethyl)-ethyl-
]carbamoylpropyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 2-amino-1,3-propanediol instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.8-1.95
(2H, m), 2.21 (2H, t, J=7.6 Hz), 2.58 (2H, t, J=7.6 Hz), 2.85-2.95
(1H, m), 3.3-3.45 (4H, m), 3.55-3.95 (9H, m), 5.0-5.1 (1H, m),
7.0-7.15 (4H, m)
Example 20
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-hydroxymethyl-1-(meth-
yl)-ethyl]carbamoylpropyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 2-amino-2-methyl-1,3-propanediol
instead of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.22 (3H,
s), 1.8-1.95 (2H, m), 2.19 (2H, t, J=7.7 Hz), 2.58 (2H, t, J=7.5
Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.55-3.9 (8H, m),
5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 21
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1,1-bis(hydroxymethyl)--
ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using tris(hydroxymethyl)aminomethane
instead of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.8-1.95
(2H, m), 2.23 (2H, t, J=7.5 Hz), 2.59 (2H, t, J=7.6 Hz), 2.85-2.95
(1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (10H, m), 5.0-5.1 (1H, m),
7.0-7.15 (4H, m)
Example 22
4-[(4-{3-[(S)-1-(Carbamoyl)ethylcarbamoyl]propyl}phenyl)methyl]-3-(.beta.--
D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using L-alanine amide hydrochloride instead
of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.32 (3H,
d, J=7.2 Hz), 1.8-1.95 (2H, m), 2.15-2.25 (2H, m), 2.58 (2H, t,
J=7.5 Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m),
4.32 (1H, q, J=7.2 Hz), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 23
4-[(4-{3-[(S)-1-Carbamoyl-2-hydroxyethylcarbamoyl]propyl}phenyl)methyl]-3--
(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using L-serine amide hydrochloride instead
of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.85-1.95
(2H, m), 2.2-2.3 (2H, m), 2.59 (2H, t, J=7.4 Hz), 2.85-2.95 (1H,
m), 3.25-3.45 (4H, m), 3.6-3.9 (6H, m), 4.4 (1H, t, J=5.2 Hz),
5.0-5.1 (1H, m), 7.05-7.15 (4H, m)
Example 24
4-[(4-{3-[1-Carbamoyl-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-3-(.-
beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using 2-amino-2-methylpropionamide instead
of glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.44 (6H,
s), 1.8-1.95 (2H, m), 2.18 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.4
Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 5.0-5.1
(1H, m), 7.0-7.15 (4H, m)
Example 25
4-[(4-{3-[2-(Acetylamino)ethylcarbamoyl]propyl}phenyl)methyl]-3-(.beta.-D--
glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using N-acetylethylenediamine instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.8-1.95
(5H, m), 2.16 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.85-2.95
(1H, m), 3.2-3.45 (8H, m), 3.6-3.9 (4H, m), 5.0-5.15 (1H, m),
7.0-7.15 (4H, m)
Example 26
4-({4-[(1E)-3-Carbamoylprop-1-enyl]phenyl}methyl)-3-(.beta.-D-glucopyranos-
yloxy)-5-isopropyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (32 mg) in
N,N-dimethylformamide (1 mL) were added ammonium chloride (8 mg),
1-hydroxybenzotriazole (9 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg)
and triethylamine (21 mg), and the mixture was stirred at room
temperature overnight. The insoluble material was removed by
filtration, 5 mol/L aqueous sodium hydroxide solution (0.5 mL) was
added to the filtrate, and the resulting mixture was stirred at
room temperature for 1 hour. The insoluble material was removed by
filtration, and the filtrate was purified by preparative reverse
phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5
.mu.m, 120 .ANG., 20.times.50 mm, flow rate 30 mL/minute linear
gradient, water/acetonitrile=90/10-10/90) to give the title
compound (7 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 2.8-2.95
(1H, m), 3.05-3.15 (2H, m), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m),
5.0-5.15 (1H, m), 6.15-6.35 (1H, m), 6.48 (1H, d, J=15.6 Hz),
7.1-7.2 (2H, m), 7.2-7.3 (2H, m)
Example 27
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{(1E)-2-[2-hydroxy-1-hydroxymethyl-1--
(methyl)-ethylcarbamoyl]vinyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 26 using 2-amino-2-methyl-1,3-propanediol and
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbo-
xyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of ammonium
chloride and
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole,
respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.3 (3H,
s), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (8H, m),
5.05-5.15 (1H, m), 6.64 (1H, d, J=15.9 Hz), 7.2-7.3 (2H, m),
7.4-7.5 (3H, m)
Example 28
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{(1E)-2-[2-hydroxy-1,1-bis(hydroxymet-
hyl)-ethylcarbamoyl]vinyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 26 using tris(hydroxymethyl)aminomethane and
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbo-
xyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of ammonium
chloride and
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole,
respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 2.85-2.95
(1H, m), 3.25-3.45 (4H, m), 3.67 (1H, dd, J=12.1 Hz, 5.3 Hz),
3.7-3.9 (9H, m), 5.05-5.15 (1H, m), 6.69 (1H, d, J=15.7 Hz), 7.24
(2H, d, J=8.3 Hz), 7.45 (2H, d, J=8.3 Hz), 7.48 (1H, d, J=15.7
Hz)
Example 29
4-[(4-{(1E)-2-[1-Carbamoyl-1-(methyl)-ethylcarbamoyl]vinyl}phenyl)methyl]--
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 26 using 2-amino-2-methylpropionamide and
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbo-
xyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of ammonium
chloride and
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole,
respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.52 (6H,
s), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.67 (1H, dd, J=11.9 Hz,
5.1 Hz), 3.7-3.9 (3H, m), 5.0-5.15 (1H, m), 6.6 (1H, d, J=15.8 Hz),
7.24 (2H, d, J=8.4 Hz), 7.4-7.5 (3H, m)
Example 30
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethylcarbamoyl)-1-(me-
thyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid
(0.5 g) in dichloromethane (5 mL) were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61
g), 1-hydroxybenzotriazole (0.43 g) and 2-aminoethanol (1.16 g),
and the mixture was stirred at room temperature overnight. To the
reaction mixture was added water, and the resulting mixture was
extracted with dichloromethane. The organic layer was washed with a
saturated aqueous sodium hydrogen carbonate solution and brine
successively, and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure, and the residue was dissolved
in methanol (5 mL). To the solution was added 10% palladium-carbon
powder (0.10 g), and the mixture was stirred at room temperature
under a hydrogen atmosphere for 4 hours. The insoluble material was
removed by filtration, and the solvent of the filtrate was removed
under reduced pressure to give
2-(2-amino-2-methylpropionylamino)ethanol (0.11 g). To a solution
of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (70 mg) in
N,N-dimethylformamide (0.5 mL) were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32
mg), 1-hydroxybenzotriazole (23 mg) and
2-(2-amino-2-methylpropionylamino)ethanol (0.11 g), and the mixture
was stirred at room temperature overnight. The insoluble material
was removed by filtration, 5 mol/L aqueous sodium hydroxide
solution (0.25 mL) was added to the filtrate, and the resulting
mixture was stirred at room temperature for 1 hour. To the mixture
was added acetic acid (0.09 mL), and the mixture was diluted with
water (1 mL). The insoluble material was removed by filtration, and
the filtrate was purified by preparative reverse phase column
chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 .mu.L, 120 .ANG.,
20.times.50 mm, flow rate 30 mL/minute linear gradient,
water/methanol=90/10-10/90) to give
3-(.beta.-D-glucopyranosyloxy)-4-(4-{(1E)-3-[1-(2-hydroxyethylcarbamoyl)--
1-methylethylcarbamoyl]prop-1-enyl}phenyl)methyl)-5-isopropyl-1H-pyrazole
(14 mg). This material was dissolved in methanol (0.5 mL). To the
solution was added 10% palladium-carbon powder (7 mg), and the
mixture was stirred at room temperature under a hydrogen atmosphere
for 2 hours. The insoluble material was removed by filtration, and
the solvent of the filtrate was removed under reduced pressure to
give the title compound (11 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.19 (2H, t, J=7.6 Hz), 2.58 (2H, t, J=7.6
Hz), 2.85-2.95 (1H, m), 3.25-3.45 (6H, m), 3.56 (2H, t, J=5.8 Hz),
3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 31
4-[(4-{3-[1-Carbamoylmethylcarbamoyl-1-(methyl)-ethylcarbamoyl]propyl}phen-
yl)methyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 30 using glycinamide hydrochloride and
triethylamine instead of 2-aminoethanol.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.22 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.7
Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (6H, m), 5.0-5.1
(1H, m), 7.0-7.15 (4H, m)
Reference Example 6
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-bromophenyl)-
methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 3 using
acetobromo-.alpha.-D-galactose instead of
acetobromo-.alpha.-D-glucose.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.17 (6H, d, J=7.3 Hz), 1.88
(3H, s), 1.99 (3H, s), 2.02 (3H, s), 2.17 (3H, s), 2.8-2.95 (1H,
m), 3.59 (1H, d, J=16.0 Hz), 3.66 (1H, d, J=16.0 Hz), 4.05-4.25
(3H, m), 5.1 (1H, dd, J=10.4 Hz, 3.5 Hz), 5.35-5.45 (2H, m), 5.57
(1H, d, J=8.2 Hz), 6.95-7.05 (2H, m), 7.3-7.4 (2H, m)
Reference Example 7
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-carb-
oxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 4 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-bromophenyl-
)methyl]-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromophenyl)m-
ethyl]-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.83 (3H,
s), 1.99 (3H, s), 2.00 (3H, s), 2.17 (3H, s), 2.8-2.95 (1H, m),
3.26 (2H, d, J=6.9 Hz), 3.6 (1H, d, J=16.2 Hz), 3.69 (1H, d, J=16.2
Hz), 4.05-4.3 (3H, m), 5.1 (1H, dd, J=10.1 Hz, 3.5 Hz), 5.3-5.5
(3H, m), 6.2-6.3 (1H, m), 6.45 (1H, d, J=15.9 Hz), 7.0-7.1 (2H, m),
7.2-7.3 (2H, m), 10.0-12.0 (1H, br)
Example 32
3-(.beta.-D-Galactopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-hydroxymethyl-1-(me-
thyl)-ethylcarbamoyl]propyl)phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and
2-amino-2-methyl-1,3-propanediol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and
glycinamide hydrochloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.22 (3H,
s), 1.8-1.95 (2H, m), 2.19 (2H, t, J=7.4 Hz), 2.58 (2H, t, J=7.5
Hz), 2.85-2.95 (1H, m), 3.52 (1H, dd, J=9.8 Hz, 3.6 Hz), 3.55-3.8
(10H, m), 3.85-3.9 (1H, m), 5.05-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 33
4-[(4-{3-[1-Carbamoyl-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-3-(.-
beta.-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and
glycinamide hydrochloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.44 (6H,
s), 1.8-1.95 (2H, m), 2.19 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.6
Hz), 2.85-2.95 (1H, m), 3.52 (1H, dd, J=9.7 Hz, 3.4 Hz), 3.55-3.65
(1H, m), 3.65-3.8 (5H, m), 3.85-3.9 (1H, m), 5.0-5.1 (1H, m),
7.0-7.15 (4H, m)
Example 34
4-({4-[3-(2-Aminoethylsulfamoyl)propyl]phenyl}methyl)-3-(.beta.-D-glucopyr-
anosyloxy)-5-isopropyl-1H-pyrazole
A suspension of sodium allylsulfonate (2.0 g) in thionyl chloride
(10.4 mL) was heated at 70.degree. C. and stirred for 1.5 days. The
insoluble material was removed by filtration, and the solvent of
the filtrate was removed under reduced pressure. The obtained
residue was dissolved in dry tetrahydrofuran (10 mL), and the
solvent was removed under reduced pressure. The obtained residue
was again dissolved in dry tetrahydrofuran (10 mL), and the solvent
was removed under reduced pressure to give allylsulfonyl chloride
(1.26 g). To a suspension of N-benzyloxycarbonyl-1,2-diaminoethane
hydrochloride (0.82 g) and triethylamine (0.63 g) in
dichloromethane (5 mL) was added allylsulfonyl chloride (0.25 g) at
room temperature, and the mixture was stirred overnight. The
reaction was quenched by addition of water, and the organic layer
of the resulting mixture was separated. The organic layer was
washed with 1 mol/L hydrochloric acid, a saturated aqueous sodium
hydrogen carbonate solution and brine successively, and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure to give N-(2-benzyloxycarbonylaminoethyl)allylsulfonamide
(82 mg). This material was dissolved in acetonitrile (0.25 mL). To
the solution were added
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromoph-
enyl)methyl]-5-isopropyl-1H-pyrazole (70 mg), triethylamine (57
mg), palladium acetate(II) (3 mg) and tris(2-methylphenyl)phosphine
(7 mg), and the mixture was refluxed overnight under shading the
light. The solvent was removed under reduced pressure, and the
residue was dissolved in methanol (0.5 mL). To this solution was
added 5 mol/L aqueous sodium hydroxide solution (0.25 mL), and the
mixture was stirred at room temperature for 1 hour. The insoluble
material was removed by filtration, and the filtrate was purified
by preparative reverse phase column chromatography (Shiseido
CAPCELL PAK UG120 ODS, 5 .mu.L, 120 .ANG., 20.times.50 mm, flow
rate 30 mL/minute linear gradient, water/methanol=90/10-10/90) to
give
4-({4-[(1E)-3-(2-benzyloxycarbonylaminoethylsulfamoyl)prop-1-enyl]phenyl}-
methyl)-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (14
mg). This material was dissolved in methanol (0.5 mL). To the
solution was added 10% palladium-carbon powder (5 mg), and the
mixture was stirred at room temperature under a hydrogen atmosphere
for 3 hours. The insoluble material was removed by filtration, and
the solvent of the filtrate was removed under reduced pressure to
give the title compound (10 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 2.0-2.1 (2H,
m), 2.65-2.75 (4H, m), 2.85-2.95 (1H, m), 2.95-3.05 (4H, m),
3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.05-7.2 (4H,
m)
Example 35
4-[(4-{3-[1-Carbamoyl-1-(methyl)-ethylsulfamoyl]propyl}phenyl)methyl]-3-(.-
beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
To a suspension of benzyl 2-amino-2-methylpropionate
p-toluenesulfonic acid salt (Tetrahedron, 1991, Vol. 47, No. 2, pp.
259-270; 3.9 g) and triethylamine (2.7 g) in dichloromethane (15
mL) was added allylsulfonyl chloride (0.75 g) at room temperature,
and the mixture was stirred overnight. The reaction was quenched by
addition of water, and the organic layer of the resulting mixture
was separated. The organic layer was washed with 1 mol/L
hydrochloric acid, a saturated aqueous sodium hydrogen carbonate
solution and brine successively, and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure to give
N-[1-benzyloxycarbonyl-1-(methyl)-ethyl]allylsulfonamide (0.48 g).
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromophenyl)m-
ethyl]-5-isopropyl-1H-pyrazole (0.40 g),
N-[1-benzyloxycarbonyl-1-(methyl)-ethyl]allylsulfonamide (0.48 g)
in acetonitrile (1 mL) were added triethylamine (0.32 g), palladium
acetate(II) (14 mg) and tris(2-methylphenyl)phosphine (39 mg), and
the mixture was refluxed overnight under shading the light. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluent:
n-hexane/ethyl acetate=1/1-ethyl acetate) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{(1E)-3-[1-be-
nzyloxycarbonyl-1-(methyl)-ethylsulfamoyl]prop-1-enyl}phenyl)methyl]-5-iso-
propyl-1H-pyrazole (0.11 g). This material was dissolved in
methanol (1 mL). To the solution was added 10% palladium-carbon
powder (50 mg), and the mixture was stirred at room temperature
under a hydrogen atmosphere for 2 hours. The insoluble material was
removed by filtration, and the solvent of the filtrate was removed
under reduced pressure to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylsulfamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
(95 mg). To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylsulfamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
(50 mg) in N,N-dimethylformamide (0.5 mL) were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg)
and 1-hydroxybenzotriazole (13 mg). An ammonia gas was bubbled into
the mixture for about 2 minutes, and the resulting mixture was
stirred at room temperature overnight. The insoluble material was
removed by filtration. To the filtrate was added 5 mol/L aqueous
sodium hydroxide solution (0.25 mL), and the mixture was stirred at
room temperature for 1 hour. To the reaction mixture was added
acetic acid (0.09 mL), and the mixture was diluted with water (1
mL). The insoluble material was removed by filtration, and the
filtrate was purified by preparative reverse phase column
chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 .mu.L, 120 .ANG.,
20.times.50 mm, flow rate 30 mL/minute linear gradient,
water/methanol=90/10-10/90) to give the title compound (14 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.43 (6H,
s), 2.0-2.15 (2H, m), 2.7 (2H, t, J=7.4 Hz), 2.8-2.95 (1H, m),
2.95-3.1 (2H, m), 3.25-3.45 (4H, m), 3.6-3.9 (4H, m), 5.0-5.15 (1H,
m), 7.05-7.2 (4H, m)
Reference Example 8
Benzyl Hydroxypivalate
To a suspension of hydroxypivalic acid (3 g) and potassium
carbonate (3.9 g) in N,N-dimethylformamide (25 mL) was added benzyl
bromide (2.9 mL), and the mixture was stirred at room temperature
for 5 hours. The reaction mixture was poured into water, and the
resulting mixture was extracted with diethyl ether. The organic
layer was washed with water twice and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure
to give the title compound (4.7 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.22 (6H, s), 2.33 (1H, t,
J=6.7 Hz), 3.58 (2H, d, J=6.7 Hz), 5.15 (2H, s), 7.3-7.4 (5H,
m)
Reference Example 9
4-(2-Benzyloxycarbonyl-2-methylpropoxy)benzaldehyde
To a solution of 4-hydroxybenzaldehyde (2.7 g), benzyl
hydroxypivalate (4.7 g) and triphenylphosphine (6.4 g) in
tetrahydrofuran (22 mL) was added diethyl azodicarboxylate (40%
toluene solution, 11 mL), and the mixture was stirred at room
temperature for 2 days. The reaction mixture was poured into water,
and the resulting mixture was extracted with diethyl ether. The
organic layer was washed with water and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography on silica gel
(eluent: n-hexane/ethyl acetate=6/1-4/1) to give the title compound
(0.97 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.36 (6H, s), 4.07 (2H, s),
5.15 (2H, s), 6.9-7.0 (2H, m), 7.2-7.35 (5H, m), 7.75-7.85 (2H, m),
9.89 (1H, s)
Reference Example 10
[4-(2-Benzyloxycarbonyl-2-methylpropoxy)phenyl]methanol
To a solution of
4-(2-benzyloxycarbonyl-2-methylpropoxy)benzaldehyde (0.97 g) in
tetrahydrofuran (20 mL) was added sodium borohydride (59 mg), and
the mixture was stirred at room temperature for 3 hours. The
reaction mixture was poured into 0.5 mol/L hydrochloric acid, and
the resulting mixture was extracted with diethyl ether. The organic
layer was washed with water and brine successively, and dried over
anhydrous magnesium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (eluent: n-hexane/ethyl acetate=6/1-3/2) to give the
title compound (0.95 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.34 (6H, s), 1.51 (1H, t,
J=5.9 Hz), 3.99 (2H, s), 4.62 (2H, d, J=5.9 Hz), 5.15 (2H, s),
6.8-6.9 (2H, m), 7.25-7.35 (7H, m)
Reference Example 11
4-{[4-(2-Benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-is-
opropyl-3H-pyrazol-3-one
To a solution of
[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methanol (0.95 g) in
tetrahydrofuran (8 mL) were added triethylamine (0.48 mL) and
methansulfonyl chloride (0.26 mL) under ice-cooling, and the
mixture was stirred for 1 hour. The insoluble material was removed
by filtration. The obtained solution of
[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl mesylate in
tetrahydrofuran was added to a suspension of sodium hydride (60%,
139 mg) and ethyl 4-methyl-3-oxopentanoate (0.52 g) in
tetrahydrofuran (15 mL), and the mixture was heated for reflux for
15 hours. To the reaction mixture was added 1 mol/L hydrochloric
acid, and the resulting mixture was extracted with diethyl ether.
The organic layer was washed with water and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure.
To a solution of the residue in ethanol (10 mL) was added hydrazine
monohydrate (0.16 mL), and the mixture was stirred at room
temperature for 2 days. The reaction mixture was concentrated under
reduced pressure, and the residue was purified by column
chromatography on silica gel (eluent:
dichloromethane/methanol=30/1-20/1) to give the title compound
(0.25 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.15 (6H, d, J=6.9 Hz), 1.32
(6H, s), 2.85-2.95 (1H, m), 3.66 (2H, s), 3.94 (2H, s), 5.13 (2H,
s), 6.7-6.8 (2H, m), 7.05-7.15 (2H, m), 7.2-7.35 (5H, m)
Reference Example 12
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyca-
rbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole
To a solution of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one (0.25 g), acetobromo-.alpha.-D-glucose
(0.48 g) and benzyltri(n-butyl)ammonium chloride (0.18 g) in
dichloromethane (5 mL) was added 5 mol/L aqueous sodium hydroxide
solution (0.35 mL), and the mixture was stirred at room temperature
for 3 hours. The reaction mixture was purified by column
chromatography on aminopropylated silica gel (eluent:
n-hexane/ethyl acetate=1/1-1/3) to give the title compound (0.28
g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.16 (6H, d, J=7.1 Hz), 1.32
(6H, s), 1.86 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s),
2.85-2.95 (1H, m), 3.56 (1H, d, J=16.0 Hz), 3.62 (1H, d, J=16.0
Hz), 3.8-3.9 (1H, m), 3.92 (1H, d, J=8.7 Hz), 3.94 (1H, d, J=8.7
Hz), 4.15 (1H, dd, J=12.5 Hz, 2.4 Hz), 4.31 (1H, dd, J=12.5 Hz, 4.2
Hz), 5.13 (2H, s), 5.15-5.3 (3H, m), 5.55-5.65 (1H, m), 6.7-6.75
(2H, m), 6.95-7.05 (2H, m), 7.25-7.35 (5H, m)
Reference Example 13
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxy-2-m-
ethylpropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyc-
arbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropy-1H-pyrazole (0.28
g) was dissolved in methanol (6 mL). To the solution was added 10%
palladium-carbon powder (54 mg), and the mixture was stirred at
room temperature under a hydrogen atmosphere overnight. The
insoluble material was removed by filtration, and the solvent of
the filtrate was removed under reduced pressure to give the title
compound (0.25 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.16 (6H, d, J=6.7 Hz), 1.33
(6H, s), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.05 (3H, s),
2.85-3.0 (1H, m), 3.54 (1H, d, J=15.8 Hz), 3.6 (1H, d, J=15.8 Hz),
3.8-3.9 (1H, m), 3.91 (1H, d, J=8.8 Hz), 3.93 (1H, d, J=8.8 Hz),
4.15 (1H, dd, J=12.5 Hz, 2.0 Hz), 4.32 (1H, dd, J=12.5H, 4.0 Hz),
5.15-5.3 (3H, m), 5.4-5.45 (1H, m), 6.7-6.8 (2H, m), 6.95-7.05 (2H,
m)
Example 36
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(car-
bamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyraz-
ole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxy-2--
methylpropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole (0.13 g) in
N,N-dimethylformamide (2 mL) were added L-alanine amide
hydrochloride (46 mg), triethylamine (0.08 mL),
1-hydroxybenzotriazole (38 mg) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11
g), and the mixture was stirred at room temperature overnight. The
reaction mixture was poured into water, and the resulting mixture
was extracted with ethyl acetate. The organic layer was washed with
water, a saturated aqueous sodium hydrogen carbonate solution,
water and brine successively, and dried over anhydrous magnesium
sulfate. The solvent was removed under reduced pressure, and the
residue was purified by column chromatography on silica gel
(eluent: dichloro-methane/methanol=20/1-10/1) to give the title
compound (0.14 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.29 (3H,
s), 1.32 (3H, s), 1.38 (3H, d, J=7.5 Hz), 1.89 (3H, s), 2.01 (3H,
s), 2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.57 (1H, d,
J=16.0 Hz), 3.62 (1H, d, J=16.0 Hz), 3.8-3.9 (2H, m), 3.94 (1H, d,
J=9.1 Hz), 4.14 (1H, dd, J=12.5 Hz, 2.4 Hz), 4.3 (1H, dd, J=12.5
Hz, 4.1 Hz), 4.4-4.55 (1H, m), 5.15-5.4 (4H, m), 5.58 (1H, d, J=8.0
Hz), 6.2-6.35 (1H, br), 6.67 (1H, d, J=7.3 Hz), 6.7-6.8 (2H, m),
7.0-7.1 (2H, m)
Example 37
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[2-hydroxy--
1,1-di-(methyl)-ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-
-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 36 using 2-amino-2-methyl-1-propanol instead
of L-alanine amide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.25 (6H,
s), 1.27 (6H, s), 1.89 (3H, s), 1.97 (3H, s), 2.01 (3H, s), 2.02
(3H, s), 2.85-3.0 (1H, m), 3.5 (2H, s), 3.6 (2H, s), 3.89 (2H, s),
3.9-4.0 (1H, m), 4.11 (1H, dd, J=12.3 Hz, 2.2 Hz), 4.3 (1H, dd,
J=12.3 Hz, 4.0 Hz), 5.05-5.15 (2H, m), 5.25-5.35 (1H, m), 5.48 (1H,
d, J=7.9 Hz), 6.75-6.9 (3H, m), 7.0-7.1 (2H, m)
Example 38
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamoy-
l-1-(methyl)-ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-
-pyrazole
The title compound was prepared in a similar manner to that
described in Example 36 using 2-amino-2-methylpropionamide instead
of L-alanine amide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.27 (6H,
s), 1.49 (6H, s), 1.89 (3H, s), 1.97 (3H, s), 2.01 (3H, s), 2.02
(3H, s), 2.85-3.0 (1H, m), 3.6 (2H, s), 3.9-4.0 (3H, m), 4.11 (1H,
dd, J=12.3 Hz, 2.4 Hz), 4.3 (1H, dd, J=12.3 Hz, 4.0 Hz), 5.05-5.15
(2H, m), 5.25-5.35 (1H, m), 5.48 (1H, d, J=8.4 Hz), 6.75-6.85 (2H,
m), 7.0-7.1 (2H, m)
Example 39
4-[(4-{2-[(S)-1-(Carbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]--
3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(ca-
rbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyra-
zole (0.14 g) in methanol (4 mL) was added sodium methoxide (28%
methanol solution, 0.04 mL), and the mixture was stirred at room
temperature for 1 hour. The reaction mixture was concentrated under
reduced pressure, and the residue was purified by solid phase
extraction on ODS (washing solvent: distilled water, eluent:
methanol) to give the title compound (94 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.29 (3H,
s), 1.3 (3H, s), 1.35 (3H, d, J=7.5 Hz), 2.8-2.95 (1H, m),
3.25-3.45 (4H, m), 3.6-3.8 (3H, m), 3.8-3.9 (1H, m), 3.94 (2H, s),
4.3-4.45 (1H, m), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15
(2H, m)
Example 40
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)-ethylca-
rbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 39 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-
-1,1-(dimethyl)-ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-
-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(ca-
rbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyra-
zole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.25 (6H,
s), 1.27 (6H, s), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.5 (2H, s),
3.6-3.7 (2H, m), 3.74 (1H, d, J=16.0 Hz), 3.8-3.95 (3H, m),
5.0-5.15 (1H, m), 6.75-6.9 (2H, m), 7.05-7.15 (2H, m)
Example 41
4-[(4-{2-[1-Carbamoyl-1-(methyl)-ethylcarbamoyl]-2-methylpropoxy}phenyl)me-
thyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 39 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamo-
yl-1-(methyl)-ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1-
H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(ca-
rbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyra-
zole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.27 (6H,
s), 1.49 (6H, s), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.8 (3H,
m), 3.8-3.9 (1H, m), 3.93 (2H, s), 5.0-5.1 (1H, m), 6.75-6.85 (2H,
m), 7.05-7.15 (2H, m)
Example 42
3-(.beta.-D-Glucopyranosyloxy)-4-([4-(3-{1-[2-hydroxy-1-(hydroxymethyl)-et-
hylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-5-isopropyl--
1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 30 using 2-amino-1,3-propanediol instead of
2-aminoethanol.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.43 (6H,
s), 1.8-1.95 (2H, m), 2.19 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5
Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.5-3.95 (9H, m),
5.0-5.15 (1H, m), 7.0-7.2 (4H, m)
Example 43
3-(.beta.-D-Glucopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1,1-bis(hydroxymethy-
l)-ethylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-5-isopr-
opyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 30 using tris(hydroxymethyl)aminomethane
instead of 2-aminoethanol.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.18 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5
Hz), 2.85-3.0 (1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (10H, m),
5.0-5.15 (1H, m), 7.0-7.2 (4H, m)
Reference Example 14
4-Bromo-2-methylbenzyl alcohol
To a solution of 4-bromo-2-methylbenzoic acid (10 g) in
tetrahydrofuran (60 mL) was added borane-dimethylsulfide complex
(7.07 g) under ice-cooling. The reaction mixture was stirred at
room temperature for 5 minutes, and stirred at 75.degree. C. for 2
days. The reaction mixture was cooled to room temperature. A
saturated aqueous potassium carbonate solution was added to the
reaction mixture, and the organic layer was separated. The organic
layer was washed with water and brine, and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure
to give the title compound (9.0 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.55-1.65 (1H, m), 2.36 (3H,
s), 4.64 (2H, d, J=5.4 Hz), 7.2-7.25 (1H, m), 7.3-7.35 (2H, m)
Reference Example 15
4-[(4-Bromo-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-on-
e
To a solution of 4-bromo-2-methylbenzyl alcohol (9.0 g) in
dichloromethane (50 mL) was added thionyl chloride (3.8 mL) under
ice-cooling, and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was concentrated under
reduced pressure to give 4-bromo-2-methylbenzyl chloride (9.8 g).
To a suspension of sodium hydride (60%, 2.1 g) in tetrahydrofuran
(90 mL) was added ethyl 4-methyl-3-oxopentanoate (7.5 g) under
ice-cooling, and the reaction mixture was stirred at room
temperature for 1 hour. 4-Bromo-2-methylbenzyl chloride (9.8 g) was
added to the reaction mixture, and the resulting mixture was
stirred at 70.degree. C. for 3 days. The reaction mixture was
poured into a saturated aqueous ammonium chloride solution, and the
mixture was extracted with diethyl ether. The organic layer was
washed with water and brine, and dried over anhydrous magnesium
sulfate. The solvent was removed under reduced pressure. To a
solution of the residue in toluene (20 mL) was added hydrazine
monohydrate (5.4 mL), and the mixture was stirred at 90.degree. C.
overnight. The reaction mixture was concentrated under reduced
pressure, and the residue was treated with n-hexane-diethyl ether
(10/1) to crystallize. The crystals were collected by filtration
and washed with n-hexane, water and n-hexane successively, and
dried under reduced pressure to give the title compound (12.4
g).
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.05 (6H, d, J=6.8 Hz),
2.28 (3H, s), 2.65-2.8 (1H, m), 3.45 (2H, s), 6.82 (1H, d, J=8.2
Hz), 7.24 (1H, dd, J=8.2 Hz, 1.8 Hz), 7.33 (1H, d, J=1.8 Hz),
8.5-12.0 (2H, br)
Reference Example 16
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromo-2-methyl-
phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 3 using
4-[(4-bromo-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-o-
ne instead of
4-[(4-bromophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.81 (3H,
s), 1.99 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 2.28 (3H, s),
2.75-2.9 (1H, m), 3.49 (1H, d, J=16.7 Hz), 3.59 (1H, d, J=16.7 Hz),
3.8-3.9 (1H, m), 4.05-4.2 (1H, m), 4.3 (1H, dd, J=12.4 Hz, 4.0 Hz),
5.1-5.3 (3H, m), 5.5-5.6 (1H, m), 6.76 (1H, d, J=8.2 Hz), 7.1-7.2
(1H, m), 7.25-7.3 (1H, m)
Reference Example 17
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbox-
yprop-1-enyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 4 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromo-2-methy-
lphenyl)methyl]-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromophenyl)m-
ethyl]-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.78 (3H,
s), 1.99 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 2.29 (3H, s),
2.75-2.9 (1H, m), 3.13 (2H, d, J=7.3 Hz), 3.54 (1H, d, J=16.8 Hz),
3.64 (1H, d, J=16.8 Hz), 3.8-3.9 (1H, m), 4.05-4.15 (1H, m),
4.25-4.35 (1H, m), 5.1-5.3 (3H, m), 5.5-5.6 (1H, m), 6.15-6.25 (1H,
m), 6.46 (1H, d, J=16.1 Hz), 6.85 (1H, d, J=7.9 Hz), 7.05 (1H, d,
J=7.9 Hz), 7.15 (1H, s)
Reference Example 18
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbox-
yvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 4 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromo-2-methy-
lphenyl)methyl]-5-isopropyl-1H-pyrazole and acrylic acid instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromophenyl)m-
ethyl]-5-isopropyl-1H-pyrazole and 3-butenoic acid,
respectively.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.73 (3H,
s), 1.99 (3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.35 (3H, s), 2.8-2.9
(1H, m), 3.58 (1H, d, J=17.2 Hz), 3.69 (1H, d, J=17.2 Hz),
3.85-3.95 (1H, m), 4.21 (1H, dd, J=12.4 Hz, 2.2 Hz), 4.35 (1H, dd,
J=12.4 Hz, 3.9 Hz), 5.15-5.3 (3H, m), 5.45 (1H, d, J=7.8 Hz), 6.4
(1H, d, J=15.8 Hz), 6.93 (1H, d, J=7.8 Hz), 7.2-7.3 (1H, m),
7.3-7.4 (1H, m), 7.69 (1H, d, J=15.8 Hz)
Example 44
4-[(4-{3-[1-Carbamoyl-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)met-
hyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and
glycinamide hydrochloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.44 (6H,
s), 1.8-1.9 (2H, m), 2.2 (2H, t, J=7.6 Hz), 2.3 (3H, s), 2.55 (2H,
t, J=7.6 Hz), 2.75-2.9 (1H, m), 3.2-3.4 (4H, m), 3.6-3.9 (4H, m),
4.95-5.1 (1H, m), 6.8-6.9 (2H, m), 6.9-7.0 (1H, m)
Example 45
4-[(4-{(1E)-2-[1-Carbamoyl-1-(methyl)-ethylcarbamoyl]vinyl}-2-methylphenyl-
)methyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 26 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbo-
xyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium
chloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.52 (6H,
s), 2.36 (3H, s), 2.75-2.9 (1H, m), 3.2-3.4 (4H, m), 3.6-3.85 (4H,
m), 5.0-5.1 (1H, m), 6.58 (1H, d, J=15.8 Hz), 7.0 (1H, d, J=7.9
Hz), 7.2-7.3 (1H, m), 7.33 (1H, s), 7.43 (1H, d, J=15.8 Hz)
Example 46
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{(1E)-2-[2-hydroxy-1-hydroxymethyl-1--
(methyl)-ethylcarbamoyl]vinyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyraz-
ole
The title compound was prepared in a similar manner to that
described in Example 26 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbo-
xyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and
2-amino-2-methyl-1,3-propanediol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium
chloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.3 (3H,
s), 2.36 (3H, s), 2.75-2.9 (1H, m), 3.25-3.45 (4H, m), 3.6-3.85
(8H, m), 5.04 (1H, d, J=6.1 Hz), 6.62 (1H, d, J=15.5 Hz), 6.99 (1H,
d, J=7.6 Hz), 7.26 (1H, d, J=7.6 Hz), 7.32 (1H, s), 7.42 (1H, d,
J=15.5 Hz)
Example 47
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{(1E)-2-[2-(sulfamoylamin-
o)ethylcarbamoyl]vinyl}-2-methylphenyl)methyl]-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 26 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbo-
xyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and
N-sulfamoylethylenediamine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium
chloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 2.36 (3H,
s), 2.75-2.9 (1H, m), 3.19 (2H, t, J=6.3 Hz), 3.25-3.4 (4H, m),
3.47 (2H, t, J=6.3 Hz), 3.6-3.7 (1H, m), 3.7-3.9 (3H, m), 5.04 (1H,
d, J=7.3 Hz), 6.54 (1H, d, J=15.7 Hz), 7.0 (1H, d, J=7.9 Hz), 7.27
(1H, d, J=7.9 Hz), 7.33 (1H, s), 7.47 (1H, d, J=15.7 Hz)
Reference Example 19
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbox-
y-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.4 g) in
N,N-dimethylformamide (2 mL) were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18
g), 1-hydroxybenzotriazole (0.13 g), benzyl
2-amino-2-methylpropionate p-toluenesulfonic acid salt (1.16 g) and
triethylamine (0.64 g) at room temperature, and the mixture was
stirred overnight. To the reaction mixture was added water, and the
resulting mixture was extracted with dichloromethane. The organic
layer was washed with water and brine, and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography on silica gel
(eluent: n-hexane/ethyl acetate=1/1-ethyl acetate) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{(1E)-3-[1--
benzyloxycarbonyl-1-(methyl)-ethylcarbamoyl]prop-1-enyl}phenyl)methyl]-5-i-
sopropyl-1H-pyrazole (0.18 g). This material was dissolved in
methanol (2 mL). To the solution was added 10% palladium-carbon
powder (50 mg), and the mixture was stirred at room temperature
under a hydrogen atmosphere for 4 hours. The insoluble material was
removed by filtration, and the solvent of the filtrate was removed
under reduced pressure to give the title compound (0.15 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.2 (6H, m), 1.57 (3H,
s), 1.59 (3H, s), 1.85 (3H, s), 1.85-1.95 (2H, m), 1.99 (3H, s),
2.02 (3H, s), 2.1-2.2 (5H, m), 2.6 (2H, t, J=7.4 Hz), 2.8-2.95 (1H,
m), 3.59 (1H, d, J=16.1 Hz), 3.68 (1H, d, J=16.1 Hz), 4.0-4.1 (1H,
m), 4.14 (1H, dd, J=11.0 Hz, 8.2 Hz), 4.27 (1H, dd, J=11.0 Hz, 5.6
Hz), 5.08 (1H, dd, J=10.3 Hz, 3.5 Hz), 5.37 (1H, d, J=8.1 Hz),
5.4-5.5 (2H, m), 6.19 (1H, s), 6.95-7.1 (4H, m)
Reference Example 20
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy--
1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 19 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.2 (6H, m), 1.57 (3H,
s), 1.58 (3H, s), 1.85 (3H, s), 1.85-1.95 (2H, m), 2.0 (3H, s),
2.03 (3H, s), 2.05 (3H, s), 2.15 (2H, t, J=7.6 Hz), 2.6 (2H, t,
J=7.5 Hz), 2.8-2.95 (1H, m), 3.58 (1H, d, J=15.7 Hz), 3.66 (1H, d,
J=15.7 Hz), 3.8-3.9 (1H, m), 4,17 (1H, dd, J=11.9 Hz, 2.2 Hz), 4.34
(1H, dd, J=11.9 Hz, 3.4 Hz), 5.15-5.3 (3H, m), 5.35-5.45 (1H, m),
6.18 (1H, s), 6.95-7.1 (4H, m)
Reference Example 21
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy--
1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-py-
razole
The title compound was prepared in a similar manner to that
described in Reference Example 19 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.15 (6H, m), 1.57 (3H,
s), 1.58 (3H, s), 1.76 (3H, s), 1.85-1.95 (2H, m), 1.99 (3H, s),
2.02 (3H, s), 2.05 (3H, s), 2.1-2.2 (2H, m), 2.25 (3H, s), 2.5-2.6
(2H, m), 2.7-2.85 (1H, m), 3.51 (1H, d, J=16.8 Hz), 3.61 (1H, d,
J=16.8 Hz), 3.8-3.9 (1H, m), 4.1-4.2 (1H, m), 4.32 (1H, dd, J=12.2
Hz, 3.4 Hz), 5.15-5.3 (3H, m), 5.38 (1H, d, J=8.1 Hz), 6.23 (1H,
s), 6.77 (1H, d, J=7.8 Hz), 6.85 (1H, d, J=7.8 Hz), 6.93 (1H,
s)
Example 48
3-(.beta.-D-Galactopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazi-
n-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]-propyl}phenyl)methyl]-5-isopro-
pyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
(30 mg) in N,N-dimethylformamide (0.5 mL) were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12
mg), 1-hydroxybenzotriazole (9 mg) and
1-(2-hydroxyethyl)-piperazine (54 mg), and the mixture was stirred
at room temperature overnight. To the reaction mixture was added 5
mol/L aqueous sodium hydroxide solution (0.25 mL), and the
resulting mixture was stirred at room temperature for 1 hour. To
the reaction mixture was added acetic acid (0.1 mL), and the
mixture was diluted with water (1 mL). The insoluble material was
removed by filtration, and the filtrate was purified by preparative
reverse phase column chromatography (Shiseido CAPCELL PAK UG120
ODS, 5 .mu.L, 120 .ANG., 20.times.50 mm, flow rate 30 mL/minute
linear gradient, water/acetonitrile=90/10-10/60) to give the title
compound (4 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.17 (2H, t, J=7.7 Hz), 2.35-2.55 (6H, m),
2.58 (2H, t, J=7.6 Hz), 2.8-2.95 (1H, m), 3.52 (1H, dd, J=9.7 Hz,
3.4 Hz), 3.55-3.8 (12H, m), 3.87 (1H, d, J=3.4 Hz), 5.08 (1H, d,
J=8.0 Hz), 7.0-7.15 (4H, m)
Example 49
3-(.beta.-D-Glucopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1-(hydroxymethyl)-et-
hylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-5-isopropyl--
1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and 2-amino-1,3-propanediol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and 1-(2-hydroxyethyl)-piperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.43 (6H,
s), 1.8-1.95 (2H, m), 2.19 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5
Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.5-3.95 (9H, m),
5.0-5.15 (1H, m), 7.0-7.2 (4H, m)
Example 50
3-(.beta.-D-Glucopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1,1-bis(hydroxymethy-
l)-ethylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-5-isopr-
opyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and tris(hydroxymethyl)aminomethane instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and 1-(2-hydroxyethyl)-piperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.18 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5
Hz), 2.85-3.0 (1H, m), 3.25-3.45 (4H, m), 3.6-3.9 (10H, m),
5.0-5.15 (1H, m), 7.0-7.2 (4H, m)
Example 51
3-(.beta.-D-Galactopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethylcarbamoyl)-1-(-
methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using 2-aminoethanol instead of
1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.42 (6H,
s), 1.8-1.9 (2H, m), 2.19 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.6
Hz), 2.8-2.95 (1H, m), 3.28 (2H, t, J=5.8 Hz), 3.45-3.65 (4H, m),
3.65-3.8 (5H, m), 3.86 (1H, d, J=2.7 Hz), 5.08 (1H, d, J=7.9 Hz),
7.0-7.15 (4H, m)
Example 52
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[2-(dimethylamino-
)ethylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazo-
le
The title compound was prepared in a similar manner to that
described in Example 48 using N,N-dimethylethylenediamine instead
of 1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.41 (6H,
s), 1.8-1.9 (2H, m), 2.19 (2H, t, J=7.7 Hz), 2.24 (6H, s), 2.42
(2H, t, J=6.8 Hz), 2.58 (2H, t, J=7.6 Hz), 2.8-2.95 (1H, m), 3.28
(2H, t, J=6.8 Hz), 3.52 (1H, dd, J=9.7 Hz, 3.3 Hz), 3.55-3.65 (1H,
m), 3.65-3.8 (5H, m), 3.8-3.9 (1H, m), 5.08 (1H, d, J=7.4 Hz),
7.0-7.15 (4H, m)
Example 53
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[2-(dimethylamino)e-
thylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and N,N-dimethylethylenediamine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and 1-(2-hydroxyethyl)-piperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.41 (6H,
s), 1.8-1.9 (2H, m), 2.18 (2H, t, J=7.5 Hz), 2.23 (6H, s), 2.41
(2H, t, J=6.8 Hz), 2.57 (2H, t, J=7.6 Hz), 2.8-2.95 (1H, m),
3.2-3.45 (6H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H,
m)
Example 54
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[3-(dimethylamino)p-
ropylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazol-
e
The title compound was prepared in a similar manner to that
described in Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and N,N-dimethyl-1,3-propanediamine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and 1-(2-hydroxyethyl)-piperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.41 (6H,
s), 1.6-1.7 (2H, m), 1.8-1.9 (2H, m), 2.19 (2H, t, J=7.7 Hz), 2.22
(6H, s), 2.35 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.85-2.95
(1H, m), 3.18 (2H, t, J=6.6 Hz), 3.3-3.45 (4H, m), 3.6-3.8 (3H, m),
3.8-3.9 (1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 55
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin--
1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-
-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole-
.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.16 (2H, t, J=7.5 Hz), 2.35-2.55 (6H, m),
2.58 (2H, t, J=7.3 Hz), 2.85-3.0 (1H, m), 3.25-3.45 (4H, m),
3.55-3.9 (10H, m), 5.0-5.15 (1H, m), 7.0-7.15 (4H, m)
Example 56
4-[(4-{3-[1-(2-Aminoethylcarbamoyl)-1-(methyl)-ethylcarbamoyl]propyl}pheny-
l)methyl]-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using ethylenediamine instead of
1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.41 (6H,
s), 1.8-1.9 (2H, m), 2.19 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.6
Hz), 2.7 (2H, t, J=5.9 Hz), 2.85-2.95 (1H, m), 3.24 (2H, t, J=5.9
Hz), 3.51 (1H, dd, J=9.8 Hz, 3.2 Hz), 3.55-3.65 (1H, m), 3.65-3.8
(5H, m), 3.86 (1H, d, J=3.2 Hz), 5.07 (1H, d, J=7.9 Hz), 7.0-7.15
(4H, m)
Example 57
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)-
carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using piperazine instead of
1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.1-2.2 (2H, m), 2.58 (2H, t, J=7.4 Hz),
2.65-2.8 (4H, m), 2.85-2.95 (1H, m), 3.45-3.8 (11H, m), 3.8-3.9
(1H, m), 5.08 (1H, d, J=8.0 Hz), 7.0-7.15 (4H, m)
Example 58
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)ca-
rbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and piperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and 1-(2-hydroxyethyl)-piperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.17 (2H, t, J=7.6 Hz), 2.5-2.85 (6H, m),
2.85-3.0 (1H, m), 3.25-3.45 (4H, m), 3.5-3.9 (8H, m), 5.0-5.15 (1H,
m), 7.0-7.15 (4H, m)
Example 59
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin--
1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5--
isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole-
.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.42 (6H,
s), 1.8-1.9 (2H, m), 2.1-2.2 (2H, m), 2.3 (3H, s), 2.35-2.6 (8H,
m), 2.75-2.9 (1H, m), 3.25-3.4 (4H, m), 3.45-3.75 (9H, m), 3.8 (1H,
d, J=11.1 Hz), 4.95-5.05 (1H, m), 6.8-7.0 (3H, m)
Example 60
3-(.beta.-D-Galactopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1,1-bis(hydroxymet-
hyl)-ethylcarbamoyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-5-iso-
propyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 48 using tris(hydroxymethyl)aminomethane
instead of 1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.18 (2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.6
Hz), 2.8-2.95 (1H, m), 3.52 (1H, dd, J=9.7 Hz, 3.4 Hz), 3.55-3.9
(13H, m), 5.07 (1H, d, J=7.5 Hz), 7.0-7.15 (4H, m)
Example 61
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperaz-
in-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyraz-
ole
The title compound was prepared in a similar manner to that
described in Example 48 using 1-methylpiperazine instead of
1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.42 (6H,
s), 1.8-1.9 (2H, m), 2.1-2.2 (2H, m), 2.25 (3H, s), 2.3-2.45 (4H,
m), 2.58 (2H, t, J=7.4 Hz), 2.85-2.95 (1H, m), 3.52 (1H, dd, J=9.6
Hz, 3.2 Hz), 3.55-3.8 (10H, m), 3.8-3.9 (1H, m), 5.08 (1H, d, J=7.4
Hz), 7.0-7.15 (4H, m)
Example 62
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-isopropylpipe-
razin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]methyl}-1H-py-
razole
The title compound was prepared in a similar manner to that
described in Example 48 using 1-isopropylpiperazine instead of
1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.03 (6H, d, J=6.6 Hz),
1.05-1.15 (6H, m), 1.42 (6H, s), 1.8-1.95 (2H, m), 2.1-2.2 (2H, m),
2.35-2.7 (7H, m), 2.8-2.95 (1H, m), 3.52 (1H, dd, J=9.8 Hz, 3.4
Hz), 3.55-3.8 (10H, m), 3.8-3.9 (1H, m), 5.08 (1H, d, J=7.8 Hz),
7.0-7.15 (4H, m)
Example 63
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[(1E)-2-{1-[2-(dimethylam-
ino)ethylcarbamoyl]-1-(methyl)-ethylcarbamoyl}vinyl]phenyl}methyl)-1H-pyra-
zole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-2-carbo-
xyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (1.2 g) in
N,N-dimethylformamide (15 mL) and dichloromethane (10 mL) was added
triethylamine (15 mL). To the mixture were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56
g), 1-hydroxybenzotriazole (0.4 g), and a solution of
2-amino-2-methylpropionic acid (2.0 g) in water (15 mL), and the
mixture was stirred at room temperature overnight. The reaction
mixture was neutralized by addition of 2 mol/L aqueous acetic acid
solution, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine successively, and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography on silica gel (eluent: ethyl
acetate-dichloromethane/methanol=7/1-3/1) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{(1E)-2-[1-ca-
rboxy-1-(methyl)-ethylcarbamoyl]vinyl}phenyl)methyl]-5-isopropyl-1H-pyrazo-
le (0.44 g). This material was dissolved in N,N-dimethylformamide
(0.3 mL). To the solution were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18
g), 1-hydroxybenzotriazole (0.13 g) and N,N-dimethylethylenediamine
(0.55 g), and the mixture was stirred at room temperature
overnight. To the reaction mixture was added 5 mol/L aqueous sodium
hydroxide solution (1.5 mL), and the mixture was stirred at room
temperature for 1 hour. To the reaction mixture was added acetic
acid (1 mL), and the mixture was diluted with water (3 mL). The
insoluble material was removed by filtration, and the filtrate was
purified by preparative reverse phase column chromatography
(Shiseido CAPCELL PAK UG120 ODS, 5 .mu.L, 120 .ANG., 20.times.50
mm, flow rate 30 mL/minute linear gradient,
water/acetonitrile=90/10-10/60) to give the title compound (71
mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.49 (6H,
s), 2.27 (6H, s), 2.46 (2H, t, J=6.7 Hz), 2.8-2.95 (1H, m),
3.25-3.45 (6H, m), 3.6-3.9 (4H, m), 5.05-5.15 (1H, m), 6.61 (1H, d,
J=15.7 Hz), 7.2-7.3 (2H, m), 7.35-7.5 (3H, m)
Example 64
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[(1E)-2-{1-[(piperazin-1--
yl)carbonyl]-1-(methyl)-ethylcarbamoyl}vinyl]phenyl}methyl)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 63 using piperazine instead of
N,N-dimethylethylenediamine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.51 (6H,
s), 2.65-2.8 (4H, m), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.5-3.9
(8H, m), 5.05-5.15 (1H, m), 6.55 (1H, d, J=15.8 Hz), 7.2-7.3 (2H,
m), 7.4-7.55 (3H, m)
Example 65
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{(1E)-2-[1-{[4-(2-hydroxyethyl)-piper-
azin-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]vinyl}phenyl)methyl]-5-isopr-
opyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 63 using 1-(2-hydroxyethyl)-piperazine instead
of N,N-dimethylethylenediamine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.51 (6H,
s), 2.35-2.65 (6H, m), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m),
3.55-3.9 (10H, m), 5.05-5.15 (1H, m), 6.55 (1H, d, J=15.8 Hz),
7.2-7.3 (2H, m), 7.4-7.5 (3H, m)
Example 66
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)-ethylcar-
bamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using (S)-2-amino-1-propanol instead of
glycinamide hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (9H, m), 1.8-1.95
(2H, m), 2.17 (2H, t, J=7.7 Hz), 2.57 (2H, t, J=7.6 Hz), 2.8-2.95
(1H, m), 3.25-3.5 (6H, m), 3.6-3.8 (3H, m), 3.83 (1H, d, J=11.9
Hz), 3.85-4.0 (1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 67
3-(.beta.-D-Galactopyranosyloxy)-4-[(4-{3-[(S)-2-hydroxy-1-(methyl)-ethylc-
arbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
(S)-2-amino-1-propanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
glycinamide hydrochloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (9H, m), 1.8-1.95
(2H, m), 2.17 (2H, t, J=7.6 Hz), 2.57 (2H, t, J=7.6 Hz), 2.85-2.95
(1H, m), 3.35-3.55 (3H, m), 3.55-3.65 (1H, m), 3.65-4.0 (7H, m),
5.0-5.15 (1H, m), 7.0-7.15 (4H, m)
Example 68
3-(.beta.-D-Galactopyranosyloxy)-4-[(4-{3-[2-hydroxy-1,1-di-(methyl)-ethyl-
carbamoyl]propyl}phenyl)methyl]-5-isoproypl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
2-amino-2-methyl-1-propanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
glycinamide hydrochloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.25 (6H,
s), 1.8-1.9 (2H, m), 2.15 (2H, t, J=7.6 Hz), 2.56 (2H, t, J=7.5
Hz), 2.8-2.95 (1H, m), 3.45-3.65 (4H, m), 3.65-3.8 (5H, m), 3.8-3.9
(1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 69
4-[(4-{3-[(S)-5-Amino-5-(carbamoyl)pentylcarbamoyl]propyl}phenyl)methyl]-3-
-(.beta.-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
(S)-2-benzyloxycarbonylamino-6-aminohexanamide hydrochloride
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
glycinamide hydrochloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.3-1.6
(5H, m), 1.6-1.75 (1H, m), 1.8-1.9 (2H, m), 2.15 (2H, t, J=7.7 Hz),
2.56 (2H, t, J=7.3 Hz), 2.8-2.95 (1H, m), 3.15 (2H, t, J=7.0 Hz),
3.28 (1H, t, J=6.4 Hz), 3.52 (1H, dd, J=9.8 Hz, 3.1 Hz), 3.55-3.65
(1H, m), 3.65-3.8 (5H, m), 3.8-3.9 (1H, m), 5.08 (1H, d, J=7.9 Hz),
7.0-7.15 (4H, m)
Example 70
4-[(4-{3-[(S)-2-Amino-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-3-(.-
beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (1.6 g) in
methanol (20 mL) was added 10% palladium-carbon powder, and the
mixture was stirred at room temperature under a hydrogen atmosphere
for 3 hours. The insoluble material was removed by filtration, and
the filtrate was concentrated under reduced pressure to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(3-carboxypro-
pyl)phenyl]methyl}-5-isopropyl-1H-pyrazole (1.5 g). This material
was dissolved in N,N-dimethylformamide (15 mL). To the solution
were added (S)-2-amino-1-propanol (0.89 g), 1-hydroxybenzotriazole
(0.48 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (0.68 g), and the mixture was stirred at room
temperature overnight. The reaction mixture was poured into water,
and the resulting mixture was extracted with dichloromethane twice.
The extracts were washed with water and brine, and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[(S)-2-hyd-
roxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazo-
le (1.64 g). The obtained
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[(S)-2-hyd-
roxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazo-
le (0.19 g) was dissolved in dichloromethane (2 mL). To the
solution were added triethylamine (0.058 mL) and methanesulfonyl
chloride (0.032 mL) under ice-cooling, and the mixture was stirred
at room temperature for 1 hour. The reaction mixture was poured
into water, and the resulting mixture was extracted with
dichloromethane twice. The extracts were washed with water and
brine, and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure. The residue was dissolved in
N,N-dimethylformamide (1 mL). To the solution was added sodium
azide (0.18 g), and the mixture was stirred at 100.degree. C.
overnight. The reaction mixture was cooled to room temperature.
Five mol/L aqueous sodium hydroxide solution (1.5 mL) was added to
the mixture, and the mixture was stirred for 1 hour. Acetic acid (1
mL) and water (2 mL) were added to the reaction mixture. The
insoluble material was removed by filtration, and the filtrate was
purified by preparative reverse phase column chromatography
(Shiseido CAPCELL PAK UG120 ODS, 5 .mu.m, 120 .ANG., 20.times.50
mm, flow rate 30 mL/minute linear gradient,
water/acetonitrile=90/10-10/90) to give
4-[(4-{3-[(1S)-2-azido-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-3--
(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (18 mg). This
material was dissolved in methanol (1 mL). To the solution was
added 10% palladium-carbon powder (0.01 g), and the mixture was
stirred at room temperature under a hydrogen atmosphere for 4
hours. The insoluble material was removed by filtration, and the
filtrate was concentrated under reduced pressure to give the title
compound (12 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (9H, m), 1.8-1.95
(2H, m), 2.1-2.25 (2H, m), 2.5-2.65 (4H, m), 2.8-2.95 (1H, m),
3.25-3.45 (4H, m), 3.6-3.9 (5H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H,
m)
Example 71
4-[(4-{3-[2-Amino-1,1-di-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-3-(-
.beta.-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
2-amino-1-benzyloxycarbonylamino-2-(methyl)propane instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
glycinamide hydrochloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.27 (6H,
s), 1.8-1.9 (2H, m), 2.16 (2H, t, J=7.7 Hz), 2.57 (2H, t, J=7.6
Hz), 2.8-2.95 (3H, m), 3.51 (1H, dd, J=9.8 Hz, 3.7 Hz), 3.55-3.65
(1H, m), 3.65-3.8 (5H, m), 3.8-3.9 (1H, m), 5.08 (1H, d, J=7.7 Hz),
7.0-7.15 (4H, m)
Example 72
4-[(4-{3-[(R)-5-Amino-1-(hydroxymethyl)pentylcarbamoyl]propyl}phenyl)methy-
l]-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 1 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
(R)-2-amino-6-benzyloxycarbonylamino-1-hexanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and
glycinamide hydrochloride, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.2-1.7
(6H, m), 1.8-1.95 (2H, m), 2.2 (2H, t, J=7.5 Hz), 2.57 (2H, t,
J=7.6 Hz), 2.65 (2H, t, J=7.3 Hz), 2.8-3.0 (1H, m), 3.4-3.65 (4H,
m), 3.65-3.95 (7H, m), 5.0-5.15 (1H, m), 7.0-7.15 (4H, m)
Example 73
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{(1E)-3-[(S)-2-hydroxy-1-(methyl)-eth-
ylcarbamoyl]prop-1-enyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 26 using (S)-2-amino-1-propanol instead of
ammonium chloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (9H, m), 2.8-2.95
(1H, m), 3.09 (2H, d, J=7.4 Hz), 3.25-3.55 (6H, m), 3.6-3.9 (4H,
m), 3.9-4.0 (1H, m), 5.05-5.15 (1H, m), 6.2-6.3 (1H, m), 6.47 (1H,
d, J=15.9 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (2H, m)
Example 74
3-(.beta.-D-Glucopyranosyloxy)-4-{[4-(3-{(S)-1-[2-hydroxy-1-(hydroxymethyl-
)-ethylcarbamoyl]ethylcarbamoyl}propyl)phenyl]methyl}-5-isopropyl-1H-pyraz-
ole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (7.13 g) in
N,N-dimethylformamide (30 mL) were added 1-hydroxybenzotriazole
(2.31 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (3.25 g) and benzyl (S)-2-aminopropionate (8.34 g),
and the mixture was stirred at room temperature overnight. The
reaction mixture was poured into water, and the resulting mixture
was extracted with ethyl acetate twice. The extracts were washed
with water and brine successively, and dried over sodium sulfate.
The solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluent:
n-hexane/ethyl acetate=1/2) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{(1E)-3-[(S)--
1-(benzyloxycarbonyl)ethylcarbamoyl]prop-1-enyl}phenyl)methyl]-5-isopropyl-
-1H-pyrazole (3.25 g). This material was dissolved in methanol (40
mL). To the solution was added 10% palladium-carbon powder (1.0 g),
and the mixture was stirred at room temperature under a hydrogen
atmosphere overnight. The insoluble material was removed by
filtration, and the filtrate was concentrated under reduced
pressure to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[(S)-1-(ca-
rboxy)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
(2.25 g). To a solution of the obtained
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[(S)-1-(ca-
rboxy)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
(0.09 g) in N,N-dimethylformamide (0.5 mL) were added
1-hydroxybenzotriazole (0.026 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.037
g) and 2-amino-1,3-propanediol (0.12 g), and the mixture was
stirred at room temperature for 1 hour. To the reaction mixture was
added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the
mixture was stirred at room temperature for 1 hour. Acetic acid
(0.3 mL) and water (1 mL) were added to the reaction mixture. The
insoluble material was removed by filtration, and the filtrate was
purified by preparative reverse phase column chromatography
(Shiseido CAPCELL PAK UG120 ODS, 5 .mu.L, 120 .ANG., 20.times.50
mm, flow rate 30 mL/minute linear gradient,
water/acetonitrile=90/10-10/90) to give the title compound (0.017
g).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.32 (3H, d,
J=6.8 Hz), 1.8-1.95 (2H, m), 2.15-2.3 (2H, m), 2.58 (2H, t, J=7.5
Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.5-3.95 (9H, m),
4.25-4.35 (1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 75
3-(1-D-Glucopyranosyloxy)-4-[(4-{3-[(S)-1-(2-hydroxyethylcarbamoyl)ethylca-
rbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 74 using 2-aminoethanol instead of
2-amino-1,3-propanediol.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.31 (3H,
d, J=7.0 Hz), 1.8-1.95 (2H, m), 2.15-2.25 (2H, m), 2.58 (2H, t,
J=7.6 Hz), 2.85-2.95 (1H, m), 3.25-3.45 (6H, m), 3.58 (2H, t, J=5.7
Hz), 3.6-3.8 (3H, m), 3.83 (1H, d, J=11.9 Hz), 4.25-4.35 (1H, m),
5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 76
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{([4-(3-{(S)-1-[(4-methylpipe-
razin-1-yl)carbonyl]ethylcarbamoyl}propyl)phenyl]methyl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 74 using 1-methylpiperazine instead of
2-amino-1,3-propanediol.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.26 (3H,
d, J=7.0 Hz), 1.8-1.95 (2H, m), 2.2 (2H, t, J=7.4 Hz), 2.25-2.55
(7H, m), 2.57 (2H, t, J=7.6 Hz), 2.8-2.95 (1H, m), 3.25-3.45 (4H,
m), 3.45-3.75 (6H, m), 3.77 (1H, d, J=16.0 Hz), 3.83 (1H, d, J=11.7
Hz), 4.75-4.9 (1H, m), 5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Example 77
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[(S)-1-{[4-(2-hydroxyethyl)-pipera-
zin-1-yl]carbonyl}ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyra-
zole
The title compound was prepared in a similar manner to that
described in Example 74 using 1-(2-hydroxyethyl)-piperazine instead
of 2-amino-1,3-propanediol.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.26 (3H,
d, J=6.9 Hz), 1.8-1.95 (2H, m), 2.2 (2H, t, J=7.4 Hz), 2.4-2.65
(8H, m), 2.85-2.95 (1H, m), 3.2-3.45 (4H, m), 3.45-3.75 (8H, m),
3.77 (1H, d, J=16.4 Hz), 3.83 (1H, d, J=11.9 Hz), 4.75-4.9 (1H, m),
5.0-5.1 (1H, m), 7.0-7.15 (4H, m)
Reference Example 22
(4-Benzyloxy-2-methylphenyl)methanol
To a solution of 4-bromo-3-methylphenol (10 g) in
N,N-dimethylformamide (50 mL) were added potassium carbonate (8.87
g) and benzylbromide (6.36 mL), and the mixture was stirred at room
temperature overnight. The reaction mixture was poured into water,
and the resulting mixture was extracted with diethyl ether. The
organic layer was washed with water and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure
to give 4-benzyloxy-1-bromo-2-methylbenzene (14.6 g). This material
was dissolved in tetrahydrofuran (200 mL). To the solution was
added n-butyl lithium (2.66 mol/L n-hexane solution, 21.7 mL) at
-78.degree. C. under an argon atmosphere, and the mixture was
stirred for 10 minutes. To the reaction mixture was added
N,N-dimethylformamide (10.1 mL), and the mixture was allowed to
warm to 0.degree. C. and stirred for 30 minutes. The reaction
mixture was poured into water, and the resulting mixture was
extracted with diethyl ether. The organic layer was washed with
water and dried over anhydrous magnesium sulfate. The solvent was
removed under reduced pressure to give
4-benzyloxy-2-methylbenzaldehyde. This material was dissolved in
ethanol (100 mL). To the solution was added sodium borohydride
(1.99 g), and the mixture was stirred at room temperature
overnight. To the reaction mixture was added methanol, and the
resulting mixture was concentrated under reduced pressure. To the
residue was added a saturated aqueous sodium hydrogen carbonate
solution, and the mixture was extracted with diethylether. The
organic layer was washed with a saturated aqueous sodium hydrogen
carbonate solution, water and brine successively, and dried over
anhydrous magnesium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (eluent: n-hexane/ethylacetate=6/1-3/1-1/1) to give the
title compound (10.5 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.37 (1H, t, J=5.8 Hz), 2.36
(3H, s), 4.64 (2H, d, J=5.8 Hz), 5.06 (2H, s), 6.79 (1H, dd, J=8.4
Hz, 2.4 Hz), 6.84 (1H, d, J=2.4 Hz), 7.23 (1H, d, J=8.4 Hz),
7.25-7.45 (5H, m)
Reference Example 23
4-[(4-Benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol--
3-one
To a solution of (4-benzyloxy-2-methylphenyl)methanol (10.5 g) in
tetrahydrofuran (80 mL) were added triethylamine (7.36 mL) and
methanesulfonyl chloride (3.91 mL) under ice-cooling. After the
mixture was stirred for 1 hour, the insoluble material was removed
by filtration. The obtained solution of
(4-benzyloxy-2-methylphenyl)methyl mesylate in tetrahydrofuran was
added to a suspension of sodium hydride (60%, 2.11 g) and ethyl
4-methyl-3-oxopentanoate (7.99 g) in tetrahydrofuran (160 mL), and
the mixture was refluxed for 15 hours. To the reaction mixture was
added 1 mol/L hydrochloric acid, and the resulting mixture was
extracted with diethyl ether. The organic layer was washed with
water and dried over anhydrous magnesium sulfate. The solvent was
removed under reduced pressure. The residue was dissolved in
toluene (30 mL). Hydrazine monohydrate (6.68 mL) was added to the
solution, and the mixture was stirred at 100.degree. C. overnight.
The reaction mixture was poured into water, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine and dried over anhydrous magnesium sulfate. The solvent was
removed under reduced pressure, and the residue was treated with
n-hexane. The precipitated crystals were collected by filtration,
and dried under reduced pressure to give the title compound (12.3
g).
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.04 (6H, d, J=6.8 Hz),
2.24 (3H, s), 2.65-2.8 (1H, m), 3.44 (2H, s), 5.02 (2H, s), 6.69
(1H, dd, J=8.7 Hz, 2.4 Hz), 6.75-6.85 (2H, m), 7.25-7.45 (5H,
m)
Reference Example 24
4-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-piva-
loyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-
-3-one and 2,3,4,6-tetra-O-pivaloyl-.alpha.-D-glucopyranosyl
bromide (Kunz, H.; Harreus, A. Liebigs Ann. Chem. 1982, 41-48
Velarde, S.; Urbina, J.; Pena, M. R. J. Org. Chem. 1996, 61,
9541-9545) instead of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one and acetobromo-.alpha.-D-glucose,
respectively.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.04 (9H, s), 1.05-1.2 (33H,
m), 2.27 (3H, s), 2.7-2.85 (1H, m), 3.45-3.6 (2H, m), 3.8-3.9 (1H,
m), 4.11 (1H, dd, J=12.6 Hz, 4.8 Hz), 4.17 (1H, dd, J=12.6 Hz, 1.8
Hz), 5.0 (2H, s), 5.15-5.3 (2H, m), 5.37 (1H, t, J=9.5 Hz), 5.65
(1H, d, J=7.8 Hz), 6.64 (1H, dd, J=8.4 Hz, 2.8 Hz), 6.77 (1H, d,
J=2.8 Hz), 6.83 (1H, d, J=8.4 Hz), 7.25-7.45 (5H, m)
Reference Example 25
4-[(4-Hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivalo-
yl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
4-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-piv-
aloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole (5 g) was dissolved
in tetrahydrofuran (18 mL). To the solution was added 10%
palladium-carbon powder (500 mg), and the mixture was stirred at
room temperature under a hydrogen atmosphere for 3 hours. The
insoluble material was removed by filtration, and the solvent of
the filtrate was removed under reduced pressure to give the title
compound (4.45 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.2 (42H, m), 2.24 (3H,
s), 2.7-2.85 (1H, m), 3.52 (2H, s), 3.8-3.9 (1H, m), 4.09 (1H, dd,
J=12.4 Hz, 4.7 Hz), 4.15 (1H, dd, J=12.4 Hz, 1.9 Hz), 4.6 (1H, s),
5.15-5.25 (2H, m), 5.36 (1H, t, J=9.2 Hz), 5.65 (1H, d, J=8.0 Hz),
6.5 (1H, dd, J=8.3 Hz, 2.9 Hz), 6.61 (1H, d, J=2.9 Hz), 6.78 (1H,
d, J=8.3 Hz)
Reference Example 26
Benzyl 4-bromobutyrate
To a mixture of 4-bromobutyric acid (1 g), benzyl alcohol (0.65 g)
and triphenyl phosphine (1.57 g) in tetrahydrofuran (12 mL) was
added diethylazodicarboxylate (40% toluene solution, 2.88 mL), and
the mixture was stirred at room temperature for 3 hours. The
reaction mixture was poured into water, and the resulting mixture
was extracted with diethylether. The extract was washed with water
and brine, and dried over anhydrous magnesium sulfate. The solvent
was removed under reduced pressure, and the residue was purified by
column chromatography on silica gel (eluent: n-hexane/ethyl
acetate=20/1) to give the title compound (0.69 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 2.15-2.25 (2H, m), 2.56 (2H,
t, J=7.1 Hz), 3.46 (2H, t, J=6.5 Hz), 5.13 (2H, s), 7.25-7.4 (5H,
m)
Reference Example 27
4-({4-[3-(Benzyloxycarbonyl)propoxy]-2-methylphenyl}methyl)-5-isopropyl-3--
(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
To a solution of
4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pival-
oyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole (0.2 g) in
N,N-dimethylformamide (3 mL) were added benzyl 4-bromobutyrate (0.1
g), cesium carbonate (0.18 g) and a catalytic amount of sodium
iodide, and the mixture was stirred at room temperature overnight.
The reaction mixture was poured into water, and the resulting
mixture was extracted with ethyl acetate. The extract was washed
with water and brine, and dried over anhydrous magnesium sulfate.
The solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluent:
n-hexane/ethyl acetate=3/1-2/1) to give the title compound (0.16
g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.04 (9H, s), 1.05-1.2 (33H,
m), 2.05-2.15 (2H, m), 2.25 (3H, s), 2.56 (2H, t, J=7.3 Hz),
2.7-2.85 (1H, m), 3.53 (2H, s), 3.8-3.9 (1H, m), 3.94 (2H, t, J=6.2
Hz), 4.1 (1H, dd, J=12.5 Hz, 4.1 Hz), 4.16 (1H, dd, J=12.5 Hz, 2.0
Hz), 5.13 (2H, s), 5.15-5.25 (2H, m), 5.36 (1H, t, J=9.6 Hz), 5.65
(1H, d, J=8.1 Hz), 6.54 (1H, dd, J=8.5 Hz, 2.7 Hz), 6.64 (1H, d,
J=2.7 Hz), 6.81 (1H, d, J=8.5 Hz), 7.25-7.4 (5H, m)
Reference Example 28
1,2-Dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one
The title compound was prepared in a similar manner to that
described in Reference Example 23 using 4-iodobenzyl alcohol
instead of (4-benzyloxy-2-methylphenyl)methanol.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.12 (6H, d, J=7.3 Hz),
2.8-2.95 (1H, m), 3.63 (2H, s), 6.9-7.0 (2H, m), 7.5-7.6 (2H,
m)
Reference Example 29
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-iodophenyl)m-
ethyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one
and acetobromo-.alpha.-D-galactose instead of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one and acetobromo-.alpha.-D-glucose,
respectively.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.15-1.2 (6H, m), 1.88 (3H,
s), 1.99 (3H, s), 2.03 (3H, s), 2.18 (3H, s), 2.8-2.95 (1H, m),
3.58 (1H, d, J=16.0 Hz), 3.65 (1H, d, J=16.0 Hz), 4.0-4.1 (1H, m),
4.15-4.25 (2H, m), 5.09 (1H, dd, J=10.7 Hz, 3.5 Hz), 5.35-5.45 (2H,
m), 5.56 (1H, d, J=8.3 Hz), 6.85-6.95 (2H, m), 7.5-7.6 (2H, m)
Reference Example 30
{4-[2-(Benzyloxycarbonyl)ethoxy]phenyl}methanol
To a mixture of 3-[4-(hydroxymethyl)phenoxy]propionic acid (0.98 g)
and potassium carbonate (0.9 g) in N,N-dimethylformamide (5 mL) was
added benzyl bromide (0.65 mL), and the mixture was stirred at room
temperature overnight. The reaction mixture was poured into water,
and the resulting mixture was extracted with diethyl ether. The
extract was washed with water and brine, and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography on silica gel
(eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound
(1.1 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.5-1.55 (1H, m), 2.85 (2H,
t, J=6.4 Hz), 4.28 (2H, t, J=6.4 Hz), 4.62 (2H, d, J=5.9 Hz), 5.18
(2H, s), 6.85-6.9 (2H, m), 7.25-7.4 (7H, m)
Reference Example 31
4-Hydroxy-2-methylbenzaldehyde
To a solution of 4-bromo-3-methylphenol (14 g) and
N,N-diisopropylamine (39.1 mL) in dichloromethane (150 mL) was
added chloromethyl methyl ether (11.4 mL) under ice-cooling, and
the mixture was stirred at room temperature for 5 days. The
reaction mixture was poured into a saturated aqueous citric acid
solution, and the resulting mixture was extracted with diethyl
ether. The extract was washed with water, 1 mol/L aqueous sodium
hydroxide solution, water and brine successively, and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure to give 4-bromo-3-methyl-1-(methoxymethoxy)benzene (16.7
g). This material was dissolved in tetrahydrofuran (250 mL). To the
solution was added n-butyl lithium (2.64 mol/L n-hexane solution,
32.7 mL) at -78.degree. C. under an argon atmosphere, and the
mixture was stirred at the same temperature for 15 minutes. To the
reaction mixture was added N,N-dimethylformamide (16.6 mL), and the
mixture was stirred under ice-cooling for 1 hour. The reaction
mixture was poured into a saturated aqueous ammonium chloride
solution, and the resulting mixture was extracted with diethyl
ether. The extract was washed with a saturated aqueous sodium
hydrogen carbonate solution and brine, and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure to
give 2-methyl-4-(methoxymethoxy)benzaldehyde (12.9 g). This
material was dissolved in tetrahydrofuran (70 mL)--methanol (10
mL). To the solution was added concentrated hydrochloric acid (6
mL), and the mixture was stirred at 50.degree. C. for 1.5 hours.
The reaction mixture was poured into a saturated aqueous sodium
hydrogen carbonate solution, and the resulting mixture was
extracted with ethyl acetate. The extract was washed with brine,
and dried over anhydrous sodium sulfate. The solvent was removed
under reduced pressure. The residue was dissolved in ethyl acetate
(30 mL) with heating at 60.degree. C. n-Hexane (100 mL) was added
to the solution gently, and the mixture was stirred at the same
temperature for 10 minutes. The mixture was cooled to room
temperature. n-Hexane (170 mL) was added to the mixture, and the
resulting mixture was stirred overnight. The precipitated crystals
were collected by filtration, and washed with n-hexane and dried
under reduced pressure to give the title compound (5.6 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 2.63 (3H, s), 5.47 (1H, s),
6.7 (1H, d, J=2.3 Hz), 6.79 (1H, dd, J=8.4 Hz, 2.3 Hz), 7.73 (1H,
d, J=8.4 Hz), 10.11 (1H, s)
Reference Example 32
4-(2-Carboxyethoxy)-2-methylbenzaldehyde
To a mixture of 4-hydroxy-2-methylbenzaldehyde (5 g) and potassium
tert-butoxide (4.12 g) in tetrahydrofuran (60 mL) was added
.beta.-propiolactone (4.6 mL), and the mixture was stirred at room
temperature for 4 hours. The reaction mixture was poured into 1
mol/L hydrochloric acid, and the resulting mixture was extracted
with ethyl acetate. The extract was washed with water and brine,
and dried over anhydrous sodium sulfate. The solvent was removed
under reduced pressure. The residue was suspended in ethyl acetate
(20 mL)--n-hexane (100 mL). The insoluble material was collected by
filtration, and washed with n-hexane and dried under reduced
pressure to give the title compound (7.2 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 2.65 (3H, s), 2.89 (2H, t,
J=6.4 Hz), 4.32 (2H, t, J=6.4 Hz), 6.76 (1H, d, J=2.5 Hz), 6.85
(1H, dd, J=8.7 Hz, 2.5 Hz), 7.76 (1H, d, J=8.7 Hz), 10.12 (1H,
s)
Reference Example 33
4-[2-(Benzyloxycarbonyl)ethoxy]-2-methylbenzaldehyde
To a suspension of 4-(2-carboxyethoxy)-2-methylbenzaldehyde (7.2 g)
and potassium carbonate (14.3 g) in N,N-dimethylformamide (70 mL)
was added benzyl bromide (8.2 mL) at room temperature, and the
mixture was stirred overnight. The reaction mixture was poured into
water, and the resulting mixture was extracted with diethyl ether.
The extract was washed with water and brine, and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1) to give the
title compound (6.47 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 2.64 (3H, s), 2.88 (2H, t,
J=6.3 Hz), 4.34 (2H, t, J=6.3 Hz), 5.19 (2H, s), 6.73 (1H, d, J=2.4
Hz), 6.83 (1H, dd, J=8.5 Hz, 2.4 Hz), 7.3-7.4 (5H, m), 7.75 (1H, d,
J=8.5 Hz), 10.12 (1H, s)
Reference Example 34
{4-[2-(Benzyloxycarbonyl)ethoxy]-2-methylphenyl}methanol
The title compound was prepared in a similar manner to that
described in Reference Example 10 using
4-[2-(benzyloxycarbonyl)ethoxy]-2-methylbenzaldehyde instead of
4-(2-benzyloxycarbonyl-2-methylpropoxy)benzaldehyde.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.38 (1H, t, J=5.7 Hz), 2.35
(3H, s), 2.84 (2H, t, J=6.4 Hz), 4.26 (2H, t, J=6.4 Hz), 4.63 (2H,
d, J=5.7 Hz), 5.18 (2H, s), 6.7-6.75 (2H, m), 7.22 (1H, d, J=8.2
Hz), 7.3-7.4 (5H, m)
Reference Example 35
4-({4-[2-(Benzyloxycarbonyl)ethoxy]phenyl}methyl)-1,2-dihydro-5-isopropyl--
3H-pyrazol-3-one
The title compound was prepared in a similar manner to that
described in Reference Example 11 using
{4-[2-(benzyloxycarbonyl)ethoxy]phenyl}methanol instead of
[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methanol.
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.05-1.1 (6H, m), 2.75-2.85
(3H, m), 3.5 (2H, s), 4.16 (2H, t, J=5.9 Hz), 5.14 (2H, s),
6.75-6.8 (2H, m), 7.0-7.05 (2H, m), 7.3-7.4 (5H, m)
Reference Example 36
4-({4-[2-(Benzyloxycarbonyl)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-3H--
pyrazol-3-one
The title compound was prepared in a similar manner to that
described in Reference Example 11 using
{4-[2-(benzyloxycarbonyl)ethoxy]-2-methylphenyl}methanol instead of
[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methanol.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.12 (6H, d, J=6.8 Hz), 2.3
(3H, s), 2.75-2.9 (3H, m), 3.6 (2H, s), 4.23 (2H, t, J=6.2 Hz),
5.17 (2H, s), 6.62 (1H, dd, J=8.5 Hz, 2.7 Hz), 6.7 (1H, d, J=2.7
Hz), 6.94 (1H, d, J=8.5 Hz), 7.25-7.4 (5H, m)
Reference Example 37
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[2-(benzyloxyc-
arbonyl)ethoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
4-({4-[2-(benzyloxycarbonyl)ethoxy]phenyl}methyl)-1,2-dihydro-5-isopropyl-
-3H-pyrazol-3-one instead of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.87 (3H,
s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.82 (2H, t, J=6.4
Hz), 2.85-2.95 (1H, m), 3.57 (1H, d, J=15.9 Hz), 3.63 (1H, d,
J=15.9 Hz), 3.8-3.9 (1H, m), 4.1-4.15 (1H, m), 4.22 (2H, t, J=6.4
Hz), 4.31 (1H, dd, J=12.4 Hz, 4.0 Hz), 5.16 (2H, s), 5.2-5.3 (3H,
m), 5.58 (1H, d, J=7.6 Hz), 6.7-6.8 (2H, m), 7.0-7.05 (2H, m),
7.3-7.4 (5H, m)
Reference Example 38
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[2-(benzylox-
ycarbonyl)ethoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
4-({4-[2-(benzyloxycarbonyl)ethoxy]phenyl}methyl)-1,2-dihydro-5-isopropyl-
-3H-pyrazol-3-one and acetobromo-.alpha.-D-galactose instead of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one and acetobromo-.alpha.-D-glucose,
respectively.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.88 (3H,
s), 1.99 (3H, s), 2.02 (3H, s), 2.17 (3H, s), 2.8-2.9 (3H, m), 3.58
(1H, d, J=16.1 Hz), 3.65 (1H, d, J=16.1 Hz), 4.0-4.25 (5H, m), 5.09
(1H, dd, J=10.4 Hz, 3.5 Hz), 5.17 (2H, s), 5.4-5.45 (2H, m), 5.55
(1H, d, J=8.2 Hz), 6.7-6.8 (2H, m), 7.0-7.05 (2H, m), 7.25-7.35
(5H, m)
Reference Example 39
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[2-(benzyloxyc-
arbonyl)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
4-({4-[2-(benzyloxycarbonyl)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-3H-
-pyrazol-3-one instead of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.15 (6H, m), 1.8 (3H,
s), 1.99 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 2.25 (3H, s),
2.7-2.85 (3H, m), 3.49 (1H, d, J=16.2 Hz), 3.59 (1H, d, J=16.2 Hz),
3.8-3.9 (1H, m), 4.12 (1H, dd, J=12.4 Hz, 2.3 Hz), 4.21 (2H, t,
J=6.6 Hz), 4.3 (1H, dd, J=12.4 Hz, 4.0 Hz), 5.15-5.3 (5H, m), 5.56
(1H, d, J=8.0 Hz), 6.57 (1H, dd, J=8.5 Hz, 2.4 Hz), 6.67 (1H, d,
J=2.4 Hz), 6.8 (1H, d, J=8.5 Hz), 7.25-7.4 (5H, m)
Reference Example 40
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyetho-
xy)phenyl]methyl}-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 13 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[2-(benzyloxy-
carbonyl)ethoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyc-
arbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.89 (3H,
s), 1.97 (3H, s), 2.0 (3H, s), 2.02 (3H, s), 2.71 (2H, t, J=6.2
Hz), 2.85-2.95 (1H, m), 3.6 (2H, s), 3.9-3.95 (1H, m), 4.1-4.15
(1H, m), 4.18 (2H, t, J=6.2 Hz), 4.3 (1H, dd, J=12.4 Hz, 4.0 Hz),
5.05-5.15 (2H, m), 5.25-5.35 (1H, m), 5.48 (1H, d, J=8.0 Hz),
6.75-6.8 (2H, m), 7.0-7.05 (2H, m)
Reference Example 41
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-{[4-(2-carboxyet-
hoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 13 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[2-(benzylo-
xycarbonyl)ethoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyc-
arbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.9 (3H, s),
1.95 (3H, s), 1.99 (3H, s), 2.16 (3H, s), 2.71 (2H, t, J=6.1 Hz),
2.85-2.95 (1H, m), 3.61 (2H, s), 4.05-4.2 (5H, m), 5.19 (1H, dd,
J=10.4 Hz, 3.5 Hz), 5.25-5.35 (1H, m), 5.4-5.45 (1H, m), 5.46 (1H,
d, J=8.1 Hz), 6.75-6.8 (2H, m), 7.0-7.05 (2H, m)
Reference Example 42
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyetho-
xy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 13 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[2-(benzyloxy-
carbonyl)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-1-{[4-(2-benzyloxyc-
arbonyl-2-methylpropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.82 (3H,
s), 1.96 (3H, s), 2.0 (3H, s), 2.02 (3H, s), 2.26 (3H, s), 2.7 (2H,
t, J=6.2 Hz), 2.75-2.9 (1H, m), 3.53 (1H, d, J=16.4 Hz), 3.58 (1H,
d, J=16.4 Hz), 3.85-3.95 (1H, m), 4.08 (1H, dd, J=12.4 Hz, 2.4 Hz),
4.17 (2H, t, J=6.2 Hz), 4.28 (1H, dd, J=12.4 Hz, 4.1 Hz), 5.0-5.15
(2H, m), 5.27 (1H, t, J=9.6 Hz), 5.43 (1H, d, J=7.9 Hz), 6.61 (1H,
dd, J=8.5 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5 Hz), 6.77 (1H, d, J=8.5
Hz)
Reference Example 43
4-{[4-(3-Carboxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-tet-
ra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 25 using
4-({4-[3-(benzyloxycarbonyl)propoxy]-2-methylphenyl}methyl)-5-isopropyl-3-
-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
instead of
4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O--
pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.04 (9H, s), 1.05-1.2 (33H,
m), 2.05-2.15 (2H, m), 2.25 (3H, s), 2.5-2.6 (2H, m), 2.7-2.8 (1H,
m), 3.52 (2H, s), 3.8-3.9 (1H, m), 3.95-4.0 (2H, m), 4.05-4.15 (1H,
m), 4.17 (1H, dd, J=12.4 Hz, 1.9 Hz), 5.15-5.3 (2H, m), 5.36 (1H,
t, J=9.4 Hz), 5.53 (1H, d, J=8.3 Hz), 6.57 (1H, dd, J=8.4 Hz, 2.7
Hz), 6.67 (1H, d, J=2.7 Hz), 6.81 (1H, d, J=8.4 Hz)
Reference Example 44
Benzyl 2-amino-2-methylpropinate hydrochloride
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionic
acid (4.06 g) in N,N-dimethylformamide (40 mL) were added potassium
carbonate (4.15 g) and benzyl bromide (2.85 mL), and the mixture
was stirred at room temperature for 2 hours. The reaction mixture
was poured into water, and the resulting mixture was extracted with
ethyl acetate. The extract was washed with water and brine, and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure. The residue (solid) was treated with n-hexane and
collected by filtration. The crystals were dried under reduced
pressure to give benzyl
2-(tert-butoxycarbonylamino)-2-methylpropionate (4.44 g).
Hydrochloric acid (4 mol/L 1,4-dioxane solution, 15 mL) was added
to the obtained benzyl
2-(tert-butoxycarbonylamino)-2-methylpropionate (4.44 g), and the
mixture was stirred at room temperature overnight. The reaction
mixture was diluted with diethyl ether, and the resulting mixture
was stirred for 1 hour. The insoluble material was collected by
filtration, and washed with diethyl ether and dried under reduced
pressure to give the title compound (3.4 g).
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.49 (6H, s), 5.25 (2H, s),
7.3-7.45 (5H, m), 8.54 (3H, brs)
Reference Example 45
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-benzylox-
ycarbonyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopr-
opyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.14 g) in
N,N-dimethylformamide (3 mL) were added benzyl
2-amino-2-methylpropionate hydrochloride (57 mg),
1-hydroxybenzotriazole (31 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg)
and triethylamine (0.087 mL), and the mixture was stirred at room
temperature for 4 hours. The reaction mixture was poured into
water, and the resulting mixture was extracted with ethyl acetate.
The extract was washed with water and brine, and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (eluent: dichloromethane/methanol=40/1-20/1) to give the
title compound (0.15 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.15 (6H, m), 1.56 (6H,
s), 1.81 (3H, s), 1.99 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.25
(3H, s), 2.6 (2H, t, J=6.1 Hz), 2.75-2.85 (1H, m), 3.5 (1H, d,
J=16.7 Hz), 3.59 (1H, d, J=16.7 Hz), 3.8-3.9 (1H, m), 4.05-4.2 (3H,
m), 4.29 (1H, dd, J=12.5 Hz, 4.0 Hz), 5.1-5.3 (5H, m), 5.56 (1H, d,
J=8.1 Hz), 6.53 (1H, brs), 6.57 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.67
(1H, d, J=2.5 Hz), 6.8 (1H, d, J=8.5 Hz), 7.25-7.4 (5H, m)
Reference Example 46
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(ben-
zyloxycarbonyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1-
H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 45 using benzyl
(S)-2-aminopropionate p-toluenesulfonic acid salt instead of benzyl
2-amino-2-methylpropionate hydrochloride.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.38 (3H,
d, J=7.3 Hz), 1.82 (3H, s), 1.95 (3H, s), 2.0 (3H, s), 2.01 (3H,
s), 2.25 (3H, s), 2.6-2.7 (2H, m), 2.75-2.9 (1H, m), 3.52 (1H, d,
J=16.5 Hz), 3.58 (1H, d, J=16.5 Hz), 3.85-3.95 (1H, m), 4.07 (1H,
dd, J=12.2 Hz, 2.5 Hz), 4.1-4.2 (2H, m), 4.27 (1H, dd, J=12.2 Hz,
4.2 Hz), 4.4-4.5 (1H, m), 5.0-5.2 (4H, m), 5.28 (1H, t, J=9.5 Hz),
5.43 (1H, d, J=7.9 Hz), 6.58 (1H, dd, J=8.5 Hz, 2.2 Hz), 6.69 (1H,
d, J=2.2 Hz), 6.76 (1H, d, J=8.5 Hz), 7.25-7.4 (5H, m)
Reference Example 47
4-[(4-{3-[1-Benzyloxycarbonyl-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylp-
henyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyrano-
syloxy)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 45 using
4-{[4-(3-carboxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-te-
tra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.2 (42H, m), 1.52 (6H,
s), 1.95-2.1 (2H, m), 2.25 (3H, s), 2.34 (2H, t, J=7.3 Hz),
2.7-2.85 (1H, m), 3.52 (2H, s), 3.8-3.95 (3H, m), 4.05-4.2 (2H, m),
5.1-5.25 (4H, m), 5.36 (1H, t, J=9.1 Hz), 5.65 (1H, d, J=8.3 Hz),
6.05 (1H, brs), 6.53 (1H, dd, J=8.2 Hz, 2.5 Hz), 6.65 (1H, d, J=2.5
Hz), 6.81 (1H, d, J=8.2 Hz), 7.25-7.4 (5H, m)
Reference Example 48
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy--
1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-py-
razole
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-benzylo-
xycarbonyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isop-
ropyl-1H-pyrazole (0.15 g) was dissolved in methanol (5 mL). To the
solution was added 10% palladium-carbon powder (50 mg), and the
mixture was stirred at room temperature under a hydrogen atmosphere
overnight. The insoluble material was removed by filtration, and
the solvent of the filtrate was removed under reduced pressure to
give the title compound (0.13 g).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.47 (6H,
s), 1.82 (3H, s), 1.96 (3H, s), 2.0 (3H, s), 2.02 (3H, s), 2.26
(3H, s), 2.6 (2H, t, J=6.3 Hz), 2.75-2.9 (1H, m), 3.52 (1H, d,
J=16.4 Hz), 3.58 (1H, d, J=16.4 Hz), 3.85-3.95 (1H, m), 4.07 (1H,
dd, J=12.4 Hz, 2.2 Hz), 4.16 (2H, t, J=6.3 Hz), 4.27 (1H, dd,
J=12.4 Hz, 4.0 Hz), 5.0-5.15 (2H, m), 5.28 (1H, t, J=9.5 Hz), 5.43
(1H, d, J=8.2 Hz), 6.61 (1H, dd, J=8.5 Hz, 2.6 Hz), 6.71 (1H, d,
J=2.6 Hz), 6.77 (1H, d, J=8.5 Hz)
Reference Example 49
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(car-
boxy)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(be-
nzyloxycarbonyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl--
1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-benzylo-
xycarbonyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isop-
ropyl-1H-pyrazole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.39 (3H,
d, J=7.3 Hz), 1.82 (3H, s), 1.96 (3H, s), 2.0 (3H, s), 2.02 (3H,
s), 2.26 (3H, s), 2.6-2.7 (2H, m), 2.75-2.9 (1H, m), 3.52 (1H, d,
J=16.6 Hz), 3.58 (1H, d, J=16.6 Hz), 3.85-3.95 (1H, m), 4.07 (1H,
dd, J=12.4 Hz, 2.5 Hz), 4.1-4.25 (2H, m), 4.27 (1H, dd, J=12.4 Hz,
4.0 Hz), 4.4 (1H, q, J=7.3 Hz), 5.0-5.15 (2H, m), 5.28 (1H, t,
J=9.4 Hz), 5.43 (1H, d, J=8.0 Hz), 6.62 (1H, dd, J=8.3 Hz, 2.7 Hz),
6.72 (1H, d, J=2.7 Hz), 6.77 (1H, d, J=8.3 Hz)
Reference Example 50
4-[(4-{3-[1-Carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)meth-
yl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-
-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 48 using
4-[(4-{3-[1-benzyloxycarbonyl-1-(methyl)-ethylcarbamoyl]propoxy}-2-methyl-
phenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyran-
osyloxy)-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-benzylo-
xycarbonyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isop-
ropyl-1H-pyrazole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (42H, m), 1.44 (6H,
s), 1.95-2.05 (2H, m), 2.26 (3H, s), 2.35 (2H, t, J=7.4 Hz),
2.75-2.85 (1H, m), 3.5-3.6 (2H, m), 3.9-4.0 (3H, m), 4.09 (1H, dd,
J=12.4 Hz, 1.8 Hz), 4.17 (1H, dd, J=12.4 Hz, 4.2 Hz), 5.05-5.2 (2H,
m), 5.39 (1H, t, J=9.5 Hz), 5.58 (1H, d, J=7.9 Hz), 6.58 (1H, dd,
J=8.4 Hz, 2.6 Hz), 6.7 (1H, d, J=2.6 Hz), 6.8 (1H, d, J=8.4 Hz)
Reference Example 51
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{4-[1-carbox-
y-1-(methyl)-ethylcarbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
A mixture of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-iodophenyl)-
methyl]-5-isopropyl-1H-pyrazole (0.43 g), 4-pentynoic acid (94 mg),
tetrakis(triphenylphosphine)palladium(0) (37 mg), copper(I)iodide
(12 mg) and tiethylamine (0.45 mL) in tetrahydrofuran (5 mL) was
stirred at room temperature under an argon atmosphere overnight.
The reaction mixture was poured into 0.5 mol/L hydrochloric acid,
and the resulting mixture was extracted with ethyl acetate. The
extract was washed with water and brine, and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography on silica gel
(eluent: n-hexane/ethyl acetate=1/2-ethyl acetate) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-{[4-(4-carboxyb-
ut-1-ynyl)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.37 g). This
material was dissolved in N,N-dimethylformamide (6 mL). To the
solution were added benzyl 2-amino-2-methylpropionate hydrochloride
(0.15 g), 1-hydroxybenzotriazole (86 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22
g) and triethylamine (0.32 mL), and the mixture was stirred at room
temperature overnight. The reaction mixture was poured into 0.5
mol/L hydrochloric acid, and the resulting mixture was extracted
with ethyl acetate. The extract was washed with water, a saturated
aqueous sodium hydrogen carbonate solution and brine successively,
and dried over anhydrous sodium sulfate. The solvent was removed
under reduced pressure, and the residue was purified by column
chromatography on silica gel (eluent:
dichloromethane/methanol=20/1) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{4-[1-benzy-
loxycarbonyl-1-(methyl)-ethylcarbamoyl]but-1-ynyl}phenyl)methyl]-5-isoprop-
yl-1H-pyrazole (0.36 g). This material was dissolved in methanol (5
mL). To the solution was added 10% palladium-carbon powder (50 mg),
and the mixture was stirred at room temperature under a hydrogen
atmosphere for 2 hours. The insoluble material was removed by
filtration, and the solvent of the filtrate was removed under
reduced pressure to give the title compound (0.31 g).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.44 (6H,
s), 1.55-1.65 (4H, m), 1.88 (3H, s), 1.95 (3H, s), 1.99 (3H, s),
2.1-2.2 (5H, m), 2.5-2.6 (2H, m), 2.85-3.0 (1H, m), 3.55-3.7 (2H,
m), 4.05-4.2 (3H, m), 5.19 (1H, dd, J=10.4 Hz, 3.5 Hz), 5.25-5.35
(1H, m), 5.4-5.45 (1H, m), 5.46 (1H, d, J=8.1 Hz), 7.0-7.1 (4H,
m)
Example 78
4-[(4-{2-[1-Carbamoyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)met-
hyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.2 g) in
N,N-dimethylformamide (3 mL) were added
2-amino-2-methylpropionamide (47 mg), 1-hydroxybenzotriazole (50
mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(118 mg) and triethylamine (0.13 mL), and the mixture was stirred
at room temperature overnight. The reaction mixture was poured into
water, and the resulting mixture was extracted with ethyl acetate.
The extract was washed with water and brine, and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-
-carbamoyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isop-
ropyl-1H-pyrazole (0.12 g). This material was dissolved in methanol
(3 mL). To the solution was added sodium methoxide (28% methanol
solution, 0.06 mL), and the mixture was stirred at room temperature
for 1 hour. To the reaction mixture was added acetic acid (0.1 mL),
and the resulting mixture was concentrated under reduced pressure.
The residue was purified by solid phase extraction on ODS (washing
solvent: distilled water, eluent: methanol) to give the title
compound (80 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.47 (6H,
s), 2.29 (3H, s), 2.62 (2H, t, J=6.1 Hz), 2.75-2.85 (1H, m),
3.25-3.4 (4H, m), 3.6-3.75 (3H, m), 3.81 (1H, d, J=11.9 Hz), 4.18
(2H, t, J=6.1 Hz), 4.95-5.05 (1H, m), 6.63 (1H, dd, J=8.4 Hz, 2.4
Hz), 6.72 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.4 Hz)
Example 79
4-[(4-{2-[1-Carbamoyl-1-(methyl)-ethylcarbamoyl]ethoxy}phenyl)methyl]-3-(.-
beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)phenyl]methyl}-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.5-1.15 (6H, m), 1.47 (6H,
s), 2.63 (2H, t, J=6.2 Hz), 2.85-2.95 (1H, m), 3.3-3.4 (4H, m),
3.6-3.75 (3H, m), 3.8-3.85 (1H, m), 4.19 (2H, t, J=6.2 Hz),
5.05-5.1 (1H, m), 6.8-6.85 (2H, m), 7.1-7.15 (2H, m)
Example 80
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)-ethylca-
rbamoyl]ethoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methyl-1-propanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.27 (6H,
s), 2.59 (2H, t, J=6.2 Hz), 2.85-2.95 (1H, m), 3.3-3.4 (4H, m),
3.57 (2H, s), 3.6-3.85 (4H, m), 4.16 (2H, t, J=6.2 Hz), 5.05-5.1
(1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)
Reference Example 52
1-(2-Amino-2-methylpropionyl)-4-methylpiperazine
To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid
(2.37 g) in tetrahydrofuran (20 mL) was added
1,1'-carbonylbis-1H-imidazole (1.78 g), and the mixture was stirred
at room temperature for 1 hour. To the reaction mixture was added
1-methylpiperazine (2.0 mL), and the mixture was stirred at
40.degree. C. for 3.5 days. To the reaction mixture was added
methanol, and the resulting mixture was concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (eluent: dichloromethane/methanol=20/1) to give
1-(2-benzyloxycarbonylamino-2-methylpropionyl)-4-methylpiperazine
(1.99 g). This material was dissolved in methanol (10 mL). To the
solution was added 10% palladium-carbon powder (0.4 g), and the
mixture was stirred at room temperature under a hydrogen atmosphere
for 3 hours. The insoluble material was removed by filtration, and
the solvent of the filtrate was removed under reduced pressure to
give the title compound (1.14 g).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.39 (6H, s), 2.3 (3H, s),
2.44 (4H, t, J=5.1 Hz), 3.77 (4H, brs)
Reference Example 53
2-(2-Amino-2-methylpropionylamino)ethanol
The title compound was prepared in a similar manner to that
described in Reference Example 52 using 2-aminoethanol instead of
1-methylpiperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.31 (6H, s), 3.25-3.35 (2H,
m), 3.6 (2H, t, J=5.8 Hz)
Example 81
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazin-
-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)phenyl]methyl}-1H-pyrazol-
e
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and
1-(2-amino-2-methylpropionyl)-4-methylpiperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.45 (6H,
s), 2.2 (3H, s), 2.3-2.5 (4H, m), 2.6 (2H, t, J=5.7 Hz), 2.85-2.95
(1H, m), 3.3-3.4 (4H, m), 3.6-3.9 (8H, m), 4.18 (2H, t, J=5.7 Hz),
5.05-5.1 (1H, m), 6.75-6.85 (2H, m), 7.1-7.15 (2H, m)
Example 82
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperaz-
in-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)phenyl]methyl}-1H-pyraz-
ole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-{[4-(2-carboxye-
thoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and
1-(2-amino-2-methylpropionyl)-4-methylpiperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.45 (6H,
s), 2.17 (3H, s), 2.35 (4H, brs), 2.6 (2H, t, J=5.6 Hz), 2.85-2.95
(1H, m), 3.52 (1H, dd, J=9.7 Hz, 3.2 Hz), 3.55-3.9 (11H, m), 4.18
(2H, t, J=5.6 Hz), 5.08 (1H, d, J=7.6 Hz), 6.75-6.85 (2H, m),
7.05-7.2 (2H, m)
Example 83
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[1-(2-hydroxyethylcarbamoyl)-1-(me-
thyl)-ethylcarbamoyl]ethoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and
2-(2-amino-2-methylpropionylamino)ethanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.45 (6H,
s), 2.63 (2H, t, J=6.2 Hz), 2.85-2.95 (1H, m), 3.24 (2H, t, J=5.9
Hz), 3.3-3.4 (4H, m), 3.51 (2H, t, J=5.9 Hz), 3.6-3.85 (4H, m),
4.19 (2H, t, J=6.2 Hz), 5.05-5.1 (1H, m), 6.8-6.85 (2H, m),
7.1-7.15 (2H, m)
Example 84
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[(S)-2-hydroxy-1-(methyl)-ethylcar-
bamoyl]ethoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and
(S)-2-amino-1-propanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (9H, m), 2.55-2.65
(2H, m), 2.85-2.95 (1H, m), 3.3-3.4 (4H, m), 3.44 (1H, dd, J=10.9
Hz, 5.7 Hz), 3.49 (1H, dd, J=10.9 Hz, 5.6 Hz), 3.6-3.75 (3H, m),
3.8-3.85 (1H, m), 3.9-4.0 (1H, m), 4.15-4.25 (2H, m), 5.0-5.1 (1H,
m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)
Example 85
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(4-methylpiperazin-
-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-1-
H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-methylpiperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.45 (6H,
s), 2.18 (3H, s), 2.29 (3H, s), 2.36 (4H, brs), 2.6 (2H, t, J=5.7
Hz), 2.75-2.85 (1H, m), 3.25-3.4 (4H, m), 3.55-3.75 (7H, m), 3.82
(1H, d, J=11.8 Hz), 4.17 (2H, t, J=5.7 Hz), 5.0-5.15 (1H, m), 6.63
(1H, dd, J=8.4 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5 Hz), 6.87 (1H, d,
J=8.4 Hz)
Example 86
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-bis(hydroxymethyl)--
ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using tris(hydroxymethyl)aminomethane
instead of 2-amino-2-methylpropionamide.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 2.29 (3H,
s), 2.68 (2H, t, J=6.1 Hz), 2.75-2.85 (1H, m), 3.25-3.4 (4H, m),
3.6-3.75 (9H, m), 3.81 (1H, d, J=12.0 Hz), 4.18 (2H, t, J=6.1 Hz),
5.0-5.05 (1H, m), 6.65 (1H, dd, J=8.4 Hz, 2.3 Hz), 6.74 (1H, d,
J=2.3 Hz), 6.86 (1H, d, J=8.4 Hz)
Example 87
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1,1-di-(methyl)-ethylca-
rbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using 2-amino-2-methyl-1-propanol instead
of 2-amino-2-methylpropionamide.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.27 (6H,
s), 2.29 (3H, s), 2.58 (2H, t, J=6.2 Hz), 2.75-2.85 (1H, m),
3.2-3.4 (4H, m), 3.57 (2H, s), 3.6-3.75 (3H, m), 3.82 (1H, d,
J=11.9 Hz), 4.16 (2H, t, J=6.2 Hz), 4.95-5.05 (1H, m), 6.62 (1H,
dd, J=8.4 Hz, 2.0 Hz), 6.72 (1H, d, J=2.0 Hz), 6.86 (1H, d, J=8.4
Hz)
Example 88
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1-hydroxymethyl-1-(meth-
yl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using 2-amino-2-methyl-1,3-propanediol
instead of 2-amino-2-methylpropionamide.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.25 (3H,
s), 2.29 (3H, s), 2.63 (2H, t, J=6.2 Hz), 2.75-2.85 (1H, m),
3.25-3.4 (4H, m), 3.6-3.7 (7H, m), 3.81 (1H, d, J=11.8 Hz), 4.17
(2H, t, J=6.2 Hz), 5.0-5.05 (1H, m), 6.63 (1H, dd, J=8.4 Hz, 2.4
Hz), 6.73 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.4 Hz)
Example 89
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[1-{[4-(2-hydroxyethyl)-piperazin--
1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]ethoxy}2-methylphenyl)methyl]-5-i-
sopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-(2-hydroxyethyl)-piperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.45 (6H,
s), 2.3 (3H, s), 2.35-2.55 (6H, m), 2.6 (2H, t, J=5.7 Hz), 2.75-2.9
(1H, m), 3.25-3.4 (4H, m), 3.57 (2H, t, J=5.8 Hz), 3.6-3.8 (7H, m),
3.82 (1H, d, J=11.9 Hz), 4.17 (2H, t, J=5.7 Hz), 5.0-5.05 (1H, m),
6.63 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.87 (1H,
d, J=8.4 Hz)
Example 90
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[1-(2-hydroxyethylcarbamoyl)-1-(me-
thyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazol-
e
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 2-aminoethanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15(6H, m), 1.45 (6H,
s), 2.29 (3H, s), 2.63 (2H, t, J=6.2 Hz), 2.75-2.85 (1H, m), 3.24
(2H, t, J=5.9 Hz), 3.3-3.4 (4H, m), 3.51 (2H, t, J=5.9 Hz), 3.6-3.7
(3H, m), 3.82 (1H, d, J=12.0 Hz), 4.18 (2H, t, J=6.2 Hz), 5.0-5.05
(1H, m), 6.64 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.74 (1H, d, J=2.4 Hz),
6.86 (1H, d, J=8.4 Hz)
Example 91
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[1-(3-hydroxypropylcarbamoyl)-1-(m-
ethyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazo-
le
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 3-amino-1-propanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.45 (6H,
s), 1.55-1.65 (2H, m), 2.29 (3H, s), 2.62 (2H, t, J=6.1 Hz),
2.75-2.85 (1H, m), 3.2 (2H, t, J=6.6 Hz), 3.25-3.4 (4H, m), 3.51
(2H, t, J=6.2 Hz), 3.6-3.7 (3H, m), 3.82 (1H, d, J=12.0 Hz), 4.18
(2H, t, J=6.1 Hz), 5.0-5.15 (1H, m), 6.64 (1H, dd, J=8.4 Hz, 2.3
Hz), 6.73 (1H, d, J=2.3 Hz), 6.87 (1H, d, J=8.4 Hz)
Example 92
4-[(4-{2-[(S)-1-(Carbamoyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-3-
-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using L-alanine amide hydrochloride instead
of 2-amino-2-methylpropionamide.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.15 (6H, m), 1.36 (3H,
d, J=7.2 Hz), 2.29 (3H, s), 2.6-2.85 (3H, m), 3.3-3.4 (4H, m),
3.6-3.7 (3H, m), 3.81 (1H, d, J=12.1 Hz), 4.15-4.25 (2H, m), 4.36
(1H, q, J=7.2 Hz), 5.0-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.5
Hz), 6.72 (1H, d, J=2.5 Hz), 6.86 (1H, d, J=8.4 Hz)
Example 93
3-(.beta.-D-Glucopyranosyloxy)-4-[4-{2-[(S)-1-(2-hydroxyethylcarbamoyl)eth-
ylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(ca-
rboxy)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazol-
e and 2-aminoethanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.34 (3H,
d, J=7.2 Hz), 2.29 (3H, s), 2.67 (2H, t, J=6.1 Hz), 2.75-2.85 (1H,
m), 3.2-3.4 (6H, m), 3.55 (2H, t, J=5.8 Hz), 3.6-3.7 (3H, m), 3.82
(1H, d, J=12.0 Hz), 4.19 (2H, t, J=6.1 Hz), 4.35 (1H, q, J=7.2 Hz),
4.95-5.05 (1H, m), 6.63 (1H, dd, J=8.4 Hz, 2.3 Hz), 6.73 (1H, d,
J=2.3 Hz), 6.86 (1H, d, J=8.4 Hz)
Example 94
4-[(4-{2-[(S)-1-Carbamoyl-2-hydroxyethylcarbamoyl]ethoxy}-2-methylphenyl)m-
ethyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using L-serine amide hydrochloride instead
of 2-amino-2-methylpropionamide.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 2.29 (3H,
s), 2.65-2.9 (3H, m), 3.25-3.4 (4H, m), 3.55-3.9 (6H, m), 4.21 (2H,
t, J=6.0 Hz), 4.4-4.5 (1H, m), 4.95-5.05 (1H, m), 6.64 (1H, dd,
J=8.3 Hz, 2.2 Hz), 6.73 (1H, d, J=2.2 Hz), 6.86 (1H, d, J=8.3
Hz)
Example 95
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1-(hydroxymethyl)-ethyl-
carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using 2-amino-1,3-propanediol instead of
2-amino-2-methylpropionamide.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 2.29 (3H,
s), 2.65 (2H, t, J=6.2 Hz), 2.75-2.85 (1H, m), 3.3-3.4 (4H, m),
3.55-3.7 (7H, m), 3.86 (1H, d, J=11.6 Hz), 3.9-4.0 (1H, m), 4.19
(2H, t, J=6.2 Hz), 4.95-5.05 (1H, m), 6.63 (1H, dd, J=8.4 Hz, 2.4
Hz), 6.72 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.4 Hz)
Example 96
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{2-[(S)-1-(3-hydroxypropylcarbamoyl)e-
thylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[(S)-1-(ca-
rboxy)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazol-
e and 3-amino-1-propanol instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.34 (3H,
d, J=7.2 Hz), 1.6-1.7 (2H, m), 2.29 (3H, s), 2.66 (2H, t, J=6.2
Hz), 2.75-2.85 (1H, m), 3.2-3.4 (6H, m), 3.54 (2H, t, J=6.2 Hz),
3.6-3.7 (3H, m), 3.82 (1H, d, J=11.6 Hz), 4.19 (2H, t, J=6.2 Hz),
4.32 (1H, q, J=7.2 Hz), 5.0-5.05 (1H, m), 6.63 (1H, dd, J=8.4 Hz,
2.5 Hz), 6.72 (1H, d, J=2.5 Hz), 6.86 (1H, d, J=8.4 Hz)
Example 97
3-(.beta.-D-Galactopyranosyloxy)-4-[(4-{4-[1-{[4-(2-hydroxyethyl)-piperazi-
n-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]butyl}phenyl)methyl]-5-isopropy-
l-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{4-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and 1-(2-hydroxyethyl)-piperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.55-1.65 (4H, m), 2.18 (2H, t, J=6.8 Hz), 2.4-2.65 (8H, m),
2.85-2.95 (1H, m), 3.5-3.8 (13H, m), 3.85-3.9 (1H, m), 5.08 (1H, d,
J=7.8 Hz), 7.04 (2H, d, J=8.0 Hz), 7.1 (2H, d, J=8.0 Hz)
Example 98
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(4-{1-[(4-methylpiperaz-
in-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}butyl)phenyl]methyl}-1H-pyrazo-
le
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{4-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and 1-methylpiperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.41 (6H,
s), 1.55-1.65 (4H, m), 2.18 (2H, t, J=6.9 Hz), 2.24 (3H, s), 2.35
(4H, brs), 2.57 (2H, t, J=6.6 Hz), 2.85-2.95 (1H, m), 3.45-3.8
(11H, m), 3.85-3.95 (1H, m), 5.08 (1H, d, J=7.7 Hz), 7.04 (2H, d,
J=7.9 Hz), 7.1 (2H, d, J=7.9 Hz)
Example 99
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{1-[(piperazin-1-yl)ca-
rbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-methylphenyl]methyl}-1H-pyrazo-
le
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole (40 mg) in N,N-dimethylformamide (1 mL) were added
1-benzylpiperazine (12 mg), 1-hydroxybenzotriazole (8 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16 mg)
and triethylamine (0.023 mL), and the mixture was stirred at room
temperature overnight. The reaction mixture was poured into water,
and the resulting mixture was extracted with ethyl acetate. The
extract was washed with water and brine, and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography on silica gel
(eluent: dichloromethane/methanol=30/1-15/1) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-{1-
-[(4-benzylpiperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}ethoxy)-2-me-
thylphenyl]methyl}-5-isopropyl-1H-pyrazole (31 mg). This material
was dissolved in methanol (3 mL). To the solution was added sodium
methoxide (28% methanol solution, 0.02 mL), and the mixture was
stirred at room temperature for 1 hour. To the reaction mixture was
added acetic acid (0.04 mL). The resulting mixture was concentrated
under reduced pressure, and the residue was purified by solid phase
extraction on ODS (washing solvent: distilled water, eluent:
methanol) to give
4-{[4-(2-{1-[(4-benzylpiperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}-
ethoxy)-2-methylphenyl]methyl}-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl--
1H-pyrazole (24 mg). This material was dissolved in methanol (3
mL). To the solution was added 10% palladium-carbon powder (10 mg),
and the mixture was stirred at room temperature under a hydrogen
atmosphere overnight. The insoluble material was removed under
reduced pressure, and the solvent of the filtrate was removed under
reduced pressure to give the title compound (20 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.45 (6H,
s), 2.3 (3H, s), 2.5-2.9 (7H, m), 3.25-3.4 (4H, m), 3.45-3.75 (7H,
m), 3.81 (1H, d, J=11.5 Hz), 4.17 (2H, t, J=5.7 Hz), 4.95-5.05 (1H,
m), 6.62 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5 Hz), 6.86
(1H, d, J=8.4 Hz)
Example 100
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(4-{1-[(piperazin-1-yl)-
carbonyl]-1-(methyl)-ethylcarbamoyl}butyl)phenyl]methyl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{4-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]butyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.41 (6H,
s), 1.5-1.65 (4H, m), 2.17 (2H, t, J=7.1 Hz), 2.58 (2H, t, J=6.8
Hz), 2.72 (4H, brs), 2.85-2.95 (1H, m), 3.45-3.8 (11H, m), 3.8-3.9
(1H, m), 5.08 (1H, d, J=7.7 Hz), 7.04 (2H, d, J=8.0 Hz), 7.1 (2H,
d, J=8.0 Hz)
Example 101
4-[(4-{2-[(S)-5-Amino-1-(carbamoyl)pentylcarbamoyl]ethoxy}-2-methylphenyl)-
methyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
(S)-2-amino-6-(benzyloxycarbonylamino)hexanamide hydrochloride
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-benzylpiperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.3-1.95
(6H, m), 2.3 (3H, s), 2.6-2.9 (5H, m), 3.3-3.4 (4H, m), 3.6-3.7
(3H, m), 3.82 (1H, d, J=11.8 Hz), 4.15-4.25 (2H, m), 4.38 (1H, dd,
J=9.3 Hz, 4.8 Hz), 5.0-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.5
Hz), 6.72 (1H, d, J=2.5 Hz), 6.86 (1H, d, J=8.4 Hz)
Example 102
4-[(4-{2-[(S)-5-Amino-5-(carbamoyl)pentylcarbamoyl]ethoxy}-2-methylphenyl)-
methyl]-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and
(S)-6-amino-2-(benzyloxycarbonylamino)hexanamide hydrochloride
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-benzylpiperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.3-1.8
(6H, m), 2.29 (3H, s), 2.59 (2H, t, J=6.1 Hz), 2.75-2.85 (1H, m),
3.21 (2H, t, J=6.9 Hz), 3.3-3.4 (5H, m), 3.6-3.7 (3H, m), 3.81 (1H,
d, J=11.5 Hz), 4.18 (2H, t, J=6.1 Hz), 5.0-5.05 (1H, m), 6.62 (1H,
dd, J=8.4 Hz, 2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.4
Hz)
Example 103
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)ca-
rbonyl]-1-(methyl)-ethylcarbamoyl}propyl)-2-methylphenyl]methyl}-1H-pyrazo-
le
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-(benzyloxycarbonyl)piperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-benzylpiperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.16 (2H, t, J=7.2 Hz), 2.3 (3H, s), 2.55
(2H, t, J=7.5 Hz), 2.65-2.9 (5H, m), 3.2-3.45 (4H, m), 3.5-3.9 (8H,
m), 4.95-5.05 (1H, m), 6.8-6.9 (2H, m), 6.9-7.0 (1H, m)
Example 104
4-{[4-(3-{1-[(S)-5-Amino-5-(carbamoyl)pentylcarbamoyl]-1-(methyl)-ethylcar-
bamoyl}propyl)phenyl]methyl}-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl--
1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
and (S)-6-amino-2-(benzyloxycarbonylamino)hexanamide hydrochloride
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-benzylpiperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.2-1.6
(11H, m), 1.6-1.75 (1H, m), 1.8-1.9 (2H, m), 2.19 (2H, t, J=7.8
Hz), 2.58 (2H, t, J=7.7 Hz), 2.85-2.95 (1H, m), 3.1-3.25 (2H, m),
3.25-3.35 (1H, m), 3.52 (1H, dd, J=9.7 Hz, 3.4 Hz), 3.55-3.65 (1H,
m), 3.65-3.8 (5H, m), 3.86 (1H, d, J=3.1 Hz), 5.08 (1H, d, J=8.0
Hz), 7.0-7.15 (4H, m)
Example 105
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)ca-
rbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-1H-pyraz-
ole
To a solution of
4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)met-
hyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1-
H-pyrazole (0.12 g) in N,N-dimethylformamide (3 mL) were added
1-(benzyloxycarbonyl)piperazine (43 mg), 1-hydroxybenzotriazole (19
mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(50 mg) and triethylamine (0.027 mL), and the mixture was stirred
at room temperature overnight. The reaction mixture was poured into
water. The precipitated crystals were collected by filtration, and
washed with water and dried under reduced pressure to give
4-[(4-{3-[1-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)-et-
hylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra--
O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole (0.14 g). This
material was dissolved in ethanol (4 mL). To the solution was added
10% palladium-carbon powder (30 mg), and the mixture was stirred at
room temperature under a hydrogen atmosphere for 1.5 hours. The
insoluble material was removed by filtration, and the solvent of
the filtrate was removed under reduced pressure. The residue was
purified by column chromatography on silica gel (eluent:
dichloromethane/methanol=10/1-5/1) to give
5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-eth-
ylcarbamoyl}propoxy)-2-methylphenyl]methyl}-3-(2,3,4,6-tetra-O-pivaloyl-.b-
eta.-D-glucopyranosyloxy)-1H-pyrazole (89 mg). This material was
dissolved in methanol (6 mL). To the solution was added sodium
methoxide (28% methanol solution, 0.087 mL), and the mixture was
stirred at 50.degree. C. for 3 hours. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by solid phase extraction on ODS (washing solvent: distilled water,
eluent: methanol) to give the title compound (54 mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.42 (6H,
s), 1.95-2.05 (2H, m), 2.29 (3H, s), 2.39 (2H, t, J=7.3 Hz),
2.55-2.9 (5H, m), 3.25-3.4 (4H, m), 3.5-3.7 (7H, m), 3.75-3.85 (1H,
m), 3.95 (2H, t, J=6.0 Hz), 5.0-5.05 (1H, m), 6.61 (1H, dd, J=8.4
Hz, 2.3 Hz), 6.71 (1H, d, J=2.3 Hz), 6.84 (1H, d, J=8.4 Hz)
Example 106
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin--
1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-
-isopropyl-1H-pyrazole
To a solution of
4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)met-
hyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranbsyloxy)-1-
H-pyrazole (40 mg) in N,N-dimethylformamide (2 mL) were added
1-(2-hydroxyethyl)-piperazine (7 mg), 1-hydroxybenzotriazole (7
mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(13 mg) and triethylamine (0.018 mL), and the mixture was stirred
at room temperature overnight. The reaction mixture was poured into
water, and the resulting mixture was extracted with ethyl acetate.
The extract was washed with water and brine, and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (eluent: dichloro-methane/methanol=15/1) to give
4-[(4-{3-[1-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1-(methyl)-
-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tet-
ra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole (27 mg). This
material was dissolved in methanol (2 mL). To the solution was
added sodium methoxide (28% methanol solution, 0.015 mL), and the
mixture was stirred at 50.degree. C. overnight. The reaction
mixture was concentrated under reduced pressure, and the residue
was purified by solid phase extraction on ODS (washing solvent:
distilled water, eluent: methanol) to give the title compound (12
mg).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.42 (6H,
s), 1.95-2.05 (2H, m), 2.29 (3H, s), 2.35-2.5 (8H, m), 2.75-2.85
(1H, m), 3.25-3.4 (4H, m), 3.55-3.75 (9H, m), 3.75-3.85 (1H, m),
3.94 (2H, t, J=6.1 Hz), 5.0-5.05 (1H, m), 6.61 (1H, dd, J=8.4 Hz,
2.4 Hz), 6.7 (1H, d, J=2.4 Hz), 6.85 (1H, d, J=8.4 Hz)
Example 107
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(4-methylpiperazin-
-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}--
1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 106 using 1-methylpiperazine instead of
1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.42 (6H,
s), 1.95-2.05 (2H, m), 2.22 (3H, s), 2.25-2.45 (9H, m), 2.75-2.85
(1H, m), 3.25-3.4 (4H, m), 3.55-3.75 (7H, m), 3.75-3.85 (1H, m),
3.95 (2H, t, J=6.0 Hz), 5.03 (1H, d, J=7.5 Hz), 6.61 (1H, dd, J=8.3
Hz, 2.6 Hz), 6.7 (1H, d, J=2.6 Hz), 6.85 (1H, d, J=8.3 Hz)
Example 108
3-(.beta.-D-Glucopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethylcarbamoyl)-1-(me-
thyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazo-
le
The title compound was prepared in a similar manner to that
described in Example 106 using 2-aminoethanol instead of
1-(2-hydroxyethyl)-piperazine.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.42 (6H,
s), 1.95-2.05 (2H, m), 2.28 (3H, s), 2.39 (2H, t, J=7.4 Hz),
2.75-2.85 (1H, m), 3.2-3.4 (6H, m), 3.56 (2H, t, J=5.9 Hz), 3.6-3.7
(3H, m), 3.75-3.85 (1H, m), 3.94 (2H, t, J=6.1 Hz), 4.95-5.05 (1H,
m), 6.61 (1H, dd, J=8.4 Hz, 2.3 Hz), 6.71 (1H, d, J=2.3 Hz), 6.85
(1H, d, J=8.4 Hz)
Reference Example 54
1-(3-Benzoyloxypropyl)-1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-
-pyrazol-3-one
To a solution of
1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one
(5 g) and imidazole (1.19 g) in N,N-dimethylformamide (20 mL) was
added triisopropylsilyl chloride (3.1 g) at room temperature, and
the mixture was stirred for 3 hours. The reaction mixture was
poured into water, and the resulting mixture was extracted with
ethyl acetate. The extract was washed with water and brine, and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure to give
4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole
(7.27 g). To a solution of obtained
4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole
(3 g) in N,N-dimethylformamide (10 mL) was added sodium hydride
(55%, 0.33 g) under ice-cooling, and the mixture was stirred for 20
minutes. To the reaction mixture were added a solution of
1-benzoyloxy-3-chloropropane (3.0 g) in N,N-dimethylformamide (10
mL) and potassium iodide (0.25 g) at the same temperature, and the
resulting mixture was stirred at room temperature overnight. The
reaction mixture was poured into water, and the mixture was
extracted with ethyl acetate. The extract was washed with water and
brine, and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was purified by
column chromatography on silica gel (eluent: n-hexane/ethyl
acetate=20/1-10/1) to give
1-(3-benzoyloxypropyl)-4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropy-
lsilyloxy-1H-pyrazole (2.55 g). This material was dissolved in
tetrahydrofuran (3 mL). To the solution was added 4 mol/L
hydrochloric acid (1,4-dioxane solution, 10 mL), and the mixture
was stirred at room temperature overnight. The reaction mixture was
diluted with ethyl acetate, and the resulting mixture was poured
into water. The organic layer was separated, and the organic layer
was washed with brine, and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure. To the residue was
added a mixed solvent of n-hexane and ethyl acetate (20/1) (10 mL),
and the mixture was stirred at room temperature for 1 hour. The
precipitated crystals were collected by filtration, and washed with
a mixed solvent of n-hexane and ethyl acetate (20/1) and dried
under reduced pressure to give the title compound (0.85 g).
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.06 (6H, d, J=7.3 Hz),
2.1-2.2 (2H, m), 2.95-3.1 (1H, m), 3.6 (2H, s), 4.02 (2H, t, J=6.9
Hz), 4.27 (2H, t, J=6.1 Hz), 6.94 (2H, d, J=8.3 Hz), 7.5-7.7 (5H,
m), 7.9-8.0 (2H, m), 9.51 (1H, s)
Reference Example 55
Benzyl 2-amino-2-methylpropionate
Benzyl 2-amino-2-methylpropionate hydrochloride (1.48 g) was
dissolved in ethyl acetate (60 mL) and a saturated aqueous sodium
hydrogen carbonate solution (20 mL), and the organic layer was
separated. The organic layer was washed with brine, and dried over
anhydrous magnesium sulfate. The solvent was removed under reduced
pressure to give the title compound (1.2 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.37 (6H, s), 5.14 (2H, s),
7.3-7.45 (5H, m)
Reference Example 56
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-1-(3-benzoyloxypro-
pyl)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-
-isopropyl-1H-pyrazole
To a mixture of
1-(3-benzoyloxypropyl)-1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3-
H-pyrazol-3-one (0.85 g), acetobromo-.alpha.-D-galactose (0.91 g)
and benzyltri(n-butyl)ammonium chloride (0.53 g) in dichloromethane
(2.55 mL) was added 5 mol/L aqueous sodium hydroxide solution (0.85
mL), and the mixture was stirred at room temperature for 6 hours.
The reaction mixture was diluted with dichloromethane, and the
mixture was poured into water. The organic layer was separated, and
washed with brine and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure. To a solution of the
residue in acetonitrile (2.5 mL) were added 3-butenoic acid (0.36
g), triethylamine (1.71 g), palladium acetate(II) (38 mg) and
tris(2-methylphenyl)phosphine (0.1 g), and the mixture was refluxed
for 3 hours. The solvent was removed under reduced pressure, and
the residue was dissolved in ethyl acetate. The solution was washed
with water. The aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with water and brine, and dried
over anhydrous sodium sulfate. The solvent was removed under
reduced pressure, and the residue was dissolved in tetrahydrofuran
(5 mL). To the solution were added benzyl
2-amino-2-methylpropionate (1.63 g), 1-hydroxybenzotriazole (0.46
g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(0.65 g), and the mixture was stirred at room temperature for 2
days. The reaction mixture was poured into water, and the resulting
mixture was extracted with ethyl acetate. The extract was washed
with water and brine, and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluent:
n-hexane/ethyl acetate=1/1) to give
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-1-(3-benzoyloxypr-
opyl)-4-[(4-{(1E)-3-[1-carboxy-1-(methyl)-ethylcarbamoyl]prop-1-enyl}pheny-
l)methyl]-5-isopropyl-1H-pyrazole (0.55 g). This material was
dissolved in methanol (5 mL). To the solution was added 10%
palladium-carbon powder (0.15 g), and the mixture was stirred at
room temperature under a hydrogen atmosphere for 3 hours. The
insoluble material was removed by filtration, and the solvent of
the filtrate was removed under reduced pressure to give the title
compound (0.48 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.53 (3H,
s), 1.54 (3H, s), 1.85-2.2 (16H, m), 2.25-2.35 (2H, m), 2.61 (2H,
t, J=7.1 Hz), 2.95-3.05 (1H, m), 3.67 (1H, d, J=16.7 Hz), 3.71 (1H,
d, J=16.7 Hz), 3.95-4.05 (1H, m), 4.05-4.2 (4H, m), 4.36 (2H, t,
J=5.7 Hz), 5.0-5.1 (1H, m), 5.3-5.45 (2H, m), 5.51 (1H, d, J=8.2
Hz), 6.19 (1H, s), 6.95-7.05 (4H, m), 7.4-7.5 (2H, m), 7.5-7.6 (1H,
m), 8.0-8.1 (2H, m)
Example 109
3-(.beta.-D-Galactopyranosyloxy)-1-(3-hydroxypropyl)-5-isopropyl-4-{[4-(3--
{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}propyl)phenyl]meth-
yl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-1-(3-benzoyloxypr-
opyl)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]--
5-isopropyl-1H-pyrazole and 1-(benzyloxycarbonyl)piperazine instead
of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-benzylpiperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.42 (6H,
s), 1.8-2.0 (4H, m), 2.17 (2H, t, J=7.7 Hz), 2.58 (2H, t, J=7.4
Hz), 2.65-2.8 (4H, m), 3.05-3.2 (1H, m), 3.45-3.9 (14H, m), 4.08
(2H, t, J=7.0 Hz), 5.11 (1H, d, J=7.8 Hz), 7.0-7.15 (4H, m)
Example 110
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(b-
enzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl-
}phenyl)methyl]-5-isopropyl-1H-pyrazole
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole
(37 g) was dissolved in N,N-dimethylformamide (180 mL). To the
solution were added 1-(benzyloxycarbonyl)piperazine (28.4 g),
1-hydroxybenzotriazole (10.5 g) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.8
g), and the mixture was stirred at room temperature overnight. The
reaction mixture was poured into water, and the resulting mixture
was extracted with ethyl acetate twice. The extracts were washed
with water and brine, and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluent:
n-hexane/ethyl acetate=1/2-ethyl acetate) to give the title
compound (40.5 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.56 (6H,
s), 1.85-1.95 (5H, m), 1.98 (3H, s), 2.02 (3H, s), 2.12 (2H, t,
J=7.5 Hz), 2.16 (3H, s), 2.58 (2H, t, J=7.5 Hz), 2.85-2.95 (1H, m),
3.4-3.55 (4H, m), 3.55-3.75 (6H, m), 4.0-4.1 (1H, m), 4.1-4.2 (2H,
m), 5.09 (1H, dd, J=10.6 Hz, 3.3 Hz), 5.14 (2H, s), 5.35-5.45 (2H,
m), 5.56 (1H, d, J=7.8 Hz), 6.39 (1H, s), 6.95-7.1 (4H, m), 7.3-7.4
(5H, m)
Example 111
4-[(4-{3-[1-{[4-(Benzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)-eth-
ylcarbamoyl]propyl}phenyl)methyl]-3-(.beta.-D-galactopyranosyloxy)-5-isopr-
opyl-1H-pyrazole
To a solution of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(-
benzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propy-
l}phenyl)methyl]-5-isopropyl-1H-pyrazole (39.5 g) in methanol (160
mL) was added sodium methoxide (28% methanol solution, 8.24 mL),
and the mixture was stirred at room temperature overnight. To the
reaction mixture was added acetic acid (2.7 mL), and the resulting
mixture was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (eluent:
dichloromethane/methanol=10/1) to give the title compound (21.3
g).
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.42 (6H,
s), 1.8-1.9 (2H, m), 2.16 (2H, t, J=7.8 Hz), 2.57 (2H, t, J=7.6
Hz), 2.8-2.95 (1H, m), 3.35-3.8 (15H, m), 3.85-3.9 (1H, m), 5.07
(1H, d, J=7.9 Hz), 5.12 (2H, s), 7.04 (2H, d, J=8.2 Hz), 7.11 (2H,
d, J=8.2 Hz), 7.25-7.4 (5H, m)
Reference Example 57
[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methanol
To a solution of tetrahydro-4H-pyran-4-ol (3.62 g) and
triethylamine (5.6 mL) in tetrahydrofuran (35 mL) was added
methanesulfonyl chloride (2.93 mL) under ice-cooling, and the
mixture was stirred at room temperature for 1 hour. The insoluble
material was removed by filtration. To the filtrate were added
N,N-dimethylformamide (70 mL), 4-benzyloxy-2-hydroxybenzaldehyde
(5.39 g) and cesium carbonate (23 g), and the mixture was stirred
at 80.degree. C. for 12 hours. The reaction mixture was poured into
water, and the resulting mixture was extracted with diethyl ether.
The extract was washed with water and brine, and dried over
anhydrous magnesium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give
4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)benzaldehyde (4.58 g).
This material was dissolved in ethanol (70 mL). To the solution was
added sodium borohydride (0.28 g) under ice-cooling, and the
mixture was stirred at room temperature for 3 hours. To the
reaction mixture was added methanol, and the resulting mixture was
concentrated under reduced pressure. A saturated aqueous sodium
hydrogen carbonate solution was added to the residue, and the
mixture was extracted with diethyl ether. The extract was washed
with a saturated aqueous sodium hydrogen carbonate solution, water
and brine successively, and dried over anhydrous magnesium sulfate.
The solvent was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluent:
n-hexane/ethyl acetate=3/1-1/1) to give the title compound (4.45
g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.75-1.85 (2H, m), 1.95-2.05
(2H, m), 2.11 (1H, t, J=6.3 Hz), 3.5-3.65 (2H, m), 3.9-4.0 (2H, m),
4.45-4.55 (1H, m), 4.63 (2H, d, J=6.3 Hz), 5.05 (2H, s), 6.5-6.6
(2H, m), 7.19 (1H, d, J=7.7 Hz), 7.3-7.45 (5H, m)
Reference Example 58
4-{[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-1,2-dihydro--
5-isopropyl-3H-pyrazol-3-one
To a solution of
[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methanol (4.45
g) in tetrahydrofuran (28 mL) were added triethylamine (2.27 mL)
and methanesulfonyl chloride (1.21 mL) under ice-cooling, and the
mixture was stirred for 1 hour. The insoluble material was removed
by filtration. The obtained solution of
[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl mesylate
in tetrahydrofuran was added to a suspension of sodium hydride
(55%, 710 mg) and methyl 4-methyl-3-oxopentanoate (2.25 g) in
tetrahydrofuran (56 mL), and the mixture was heated for reflux for
8 hours. To the reaction mixture was added 1 mol/L hydrochloric
acid, and the resulting mixture was extracted with diethyl ether.
The organic layer was washed with water, and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure.
To a solution of the residue in toluene (8 mL) was added hydrazine
monohydrate (3.43 mL), and the mixture was stirred at 100.degree.
C. for 8 hours. The reaction mixture was purified by column
chromatography on silica gel (eluent:
dichloromethane/methanol=20/1-10/1) to give the title compound
(1.69 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.16 (6H, d, J=7.1 Hz),
1.75-1.9 (2H, m), 1.95-2.1 (2H, m), 2.9-3.05 (1H, m), 3.5-3.6 (2H,
m), 3.64 (2H, s), 3.9-4.05 (2H, m), 4.4-4.5 (1H, m), 5.0 (2H, s),
6.45-6.55 (2H, m), 7.0 (1H, d, J=8.4 Hz), 7.25-7.45 (5H, m)
Reference example 59
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-benzyloxy-2--
methylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-
-3-one and acetobromo-.alpha.-D-galactose instead of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one and acetobromo-.alpha.-D-glucose,
respectively.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.2 (6H, m), 1.78 (3H,
s), 1.98 (3H, s), 2.03 (3H, s), 2.16 (3H, s), 2.28 (3H, s),
2.75-2.85 (1H, m), 3.51 (1H, d, J=16.4 Hz), 3.62 (1H, d, J=16.4
Hz), 4.0-4.1 (1H, m), 4.1-4.2 (2H, m), 5.02 (2H, s), 5.07 (1H, dd,
J=10.4 Hz, 3.5 Hz), 5.35-5.45 (2H, m), 5.51 (1H, d, J=7.9 Hz), 6.66
(1H, dd, J=8.3 Hz, 2.8 Hz), 6.75-6.85 (2H, m), 7.2-7.45 (5H, m)
Reference Example 60
4-{[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl--
3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-1,2-dihydro-
-5-isopropyl-3H-pyrazol-3-one and
2,3,4,6-tetra-O-pivaloyl-.alpha.-D-glucopyranosyl bromide instead
of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one and acetobromo-.alpha.-D-glucose,
respectively.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.2 (42H, m), 1.7-1.85
(2H, m), 1.95-2.05 (2H, m), 2.85-2.95 (1H, m), 3.5-3.65 (4H, m),
3.8-3.9 (1H, m), 3.9-4.0 (2H, m), 4.12 (1H, dd, J=12.4 Hz, 5.1 Hz),
4.19 (1H, dd, J=12.4 Hz, 1.8 Hz), 4.4-4.5 (1H, m), 4.99 (2H, s),
5.15-5.3 (2H, m), 5.36 (1H, t, J=9.4 Hz), 5.66 (1H, d, J=8.0 Hz),
6.42 (1H, dd, J=8.3 Hz, 2.3 Hz), 6.47 (1H, d, J=2.3 Hz), 6.86 (1H,
d, J=8.3 Hz), 7.25-7.45 (5H, m)
Reference Example 61
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-hydroxy-2-me-
thylphenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 25 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-benzyloxy-2-
-methylphenyl)methyl]-5-isopropyl-1H-pyrazole instead of
4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-piv-
aloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.83 (3H,
s), 1.98 (3H, s), 2.03 (3H, s), 2.16 (3H, s), 2.25 (3H, s),
2.75-2.9 (1H, m), 3.5 (1H, d, J=16.6 Hz), 3.6 (1H, d, J=16.6 Hz),
4.0-4.05 (1H, m), 4.1-4.2 (2H, m), 4.78 (1H, brs), 5.06 (1H, dd,
J=10.4 Hz, 3.5 Hz), 5.35-5.45 (2H, m), 5.5 (1H, d, J=8.2 Hz), 6.52
(1H, dd, J=8.1 Hz, 2.6 Hz), 6.62 (1H, d, J=2.6 Hz), 6.76 (1H, d,
J=8.1 Hz)
Reference Example 62
4-{[4-Hydroxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3--
(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 25 using
4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-
-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
instead of
4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-piv-
aloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.2 (42H, m), 1.75-1.9
(2H, m), 1.95-2.1 (2H, m), 2.8-2.95 (1H, m), 3.52 (1H, d, J=16.5
Hz), 3.55-3.65 (3H, m), 3.8-3.9 (1H, m), 3.9-4.05 (2H, m), 4.05-4.2
(2H, m), 4.4-4.5 (1H, m), 5.14 (1H, brs), 5.15-5.3 (2H, m), 5.3-5.4
(1H, m), 5.65 (1H, d, J=8.1 Hz), 6.22 (1H, dd, J=8.2 Hz, 2.3 Hz),
6.37 (1H, d, J=2.3 Hz), 6.78 (1H, d, J=8.2 Hz)
Reference Example 63
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[3-(benzylox-
ycarbonyl)propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 27 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-hydroxy-2-m-
ethylphenyl)methyl]-5-isopropyl-1H-pyrazole instead of
4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pival-
oyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.15 (6H, m), 1.81 (3H,
s), 1.98 (3H, s), 2.02 (3H, s), 2.05-2.15 (2H, m), 2.16 (3H, s),
2.26 (3H, s), 2.56 (2H, t, J=7.1 Hz), 2.7-2.85 (1H, m), 3.5 (1H, d,
J=16.5 Hz), 3.6 (1H, d, J=16.5 Hz), 3.9-4.0 (2H, m), 4.0-4.1 (1H,
m), 4.1-4.2 (2H, m), 5.07 (1H, dd, J=10.6 Hz, 3.6 Hz), 5.13 (2H,
s), 5.35-5.45 (2H, m), 5.52 (1H, d, J=8.2 Hz), 6.55 (1H, dd, J=8.6
Hz, 2.5 Hz), 6.66 (1H, d, J=2.5 Hz), 6.79 (1H, d, J=8.6 Hz),
7.25-7.4 (5H, m)
Reference Example 64
4-({4-[3-(Benzyloxycarbonyl)propoxy]-2-(tetrahydro-4H-pyran-4-yloxy)phenyl-
}methyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosylox-
y)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 27 using
4-{[4-hydroxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-
-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
instead of
4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pi-
valoyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.2 (42H, m), 1.75-1.85
(2H, m), 1.95-2.15 (4H, m), 2.56 (2H, t, J=7.3 Hz), 2.8-2.95 (1H,
m), 3.5-3.65 (4H, m), 3.8-3.9 (1H, m), 3.9-4.05 (4H, m), 4.05-4.25
(2H, m), 4.4-4.5 (1H, m), 5.13 (2H, s), 5.15-5.3 (2H, m), 5.36 (1H,
t, J=9.5 Hz), 5.66 (1H, d, J=8.1 Hz), 6.3 (1H, dd, J=8.4 Hz, 2.5
Hz), 6.38 (1H, d, J=2.5 Hz), 6.84 (1H, d, J=8.4 Hz), 7.25-7.4 (5H,
m)
Reference Example 65
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-{[4-(3-carboxypr-
opoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 25 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[3-(benzylo-
xycarbonyl)propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole
instead of
4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O--
pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.15 (6H, m), 1.78 (3H,
s), 1.98 (3H, s), 2.02 (3H, s), 2.05-2.15 (2H, m), 2.16 (3H, s),
2,27 (3H, s), 2.45-2.6 (2H, m), 2.75-2.85 (1H, m), 3.49 (1H, d,
J=16.8 Hz), 3.6 (1H, d, J=16.8 Hz), 3.98 (2H, t, J=6.3 Hz), 4.0-4.1
(1H, m), 4.1-4.25 (2H, m), 5.06 (1H, dd, J=10.3 Hz, 3.4 Hz),
5.3-5.45 (3H, m), 6.58 (1H, dd, J=8.6 Hz, 2.4 Hz), 6.68 (1H, d,
J=2.4 Hz), 6.78 (1H, d, J=8.6 Hz)
Reference Example 66
4-{[4-(3-Carboxypropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-i-
sopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazo-
le
The title compound was prepared in a similar manner to that
described in Reference Example 25 using
4-({4-[3-(benzyloxycarbonyl)propoxy]-2-(tetrahydro-4H-pyran-4-yloxy)pheny-
l}methyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosylo-
xy)-1H-pyrazole instead of
4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-piv-
aloyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.2 (42H, m), 1.75-1.9
(2H, m), 1.95-2.15 (4H, m), 2.5-2.6 (2H, m), 2.8-2.95 (1H, m),
3.45-3.65 (4H, m), 3.8-3.9 (1H, m), 3.9-4.05 (4H, m), 4.1-4.25 (2H,
m), 4.4-4.55 (1H, m), 5.2-5.3 (2H, m), 5.36 (1H, t, J=9.2 Hz), 5.52
(1H, d, J=7.7 Hz), 6.33 (1H, dd, J=8.1 Hz, 2.1 Hz), 6.41 (1H, d,
J=2.1 Hz), 6.84 (1H, d, J=8.1 Hz)
Reference Example 67
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-benzyl-
oxycarbonyl-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-is-
opropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 45 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-{[4-(3-carboxyp-
ropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.15 (6H, m), 1.53 (6H,
s), 1.83 (3H, s), 1.95-2.1 (8H, m), 2.15 (3H, s), 2.26 (3H, s),
2.34 (2H, t, J=7.2 Hz), 2.7-2.85 (1H, m), 3.5 (1H, d, J=16.6 Hz),
3.6 (1H, d, J=16.6 Hz), 3.85-3.95 (2H, m), 4.0-4.1 (1H, m), 4.1-4.2
(2H, m), 5.07 (1H, dd, J=10.4 Hz, 3.5 Hz), 5.15 (2H, s), 5.35-5.45
(2H, m), 5.52 (1H, d, J=8.1 Hz), 6.06 (1H, s), 6.55 (1H, dd, J=8.5
Hz, 2.6 Hz), 6.66 (1H, d, J=2.6 Hz), 6.79 (1H, d, J=8.5 Hz),
7.25-7.4 (5H, m)
Reference Example 68
4-{[4-{3-[1-Benzyloxycarbonyl-1-(methyl)-ethylcarbamoyl]propoxy}-2-(tetrah-
ydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivalo-
yl-.beta.-D-glucopyranosyloxy)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 45 using
4-{[4-(3-carboxypropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5--
isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1H-pyraz-
ole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.2 (42H, m), 1.54 (6H,
s), 1.75-1.85 (2H, m), 2.0-2.1 (4H, m), 2.34 (2H, t, J=7.2 Hz),
2.8-2.95 (1H, m), 3.5-3.65 (4H, m), 3.8-4.05 (5H, m), 4.05-4.25
(2H, m), 4.4-4.5 (1H, m), 5.1-5.3 (4H, m), 5.36 (1H, t, J=9.5 Hz),
5.65 (1H, d, J=7.5 Hz), 6.09 (1H, brs), 6.29 (1H, dd, J=8.3 Hz, 2.2
Hz), 6.4 (1H, d, J=2.2 Hz), 6.83 (1H, d, J=8.3 Hz), 7.25-7.4 (5H,
m)
Reference Example 69
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbox-
y-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-
-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 48 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-benzy-
loxycarbonyl-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-i-
sopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-benzylo-
xycarbonyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isop-
ropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.05-1.15 (6H, m), 1.55 (3H,
s), 1.56 (3H, s), 1.79 (3H, s), 1.98 (3H, s), 2.0-2.2 (8H, m), 2.26
(3H, s), 2.4 (2H, t, J=6.9 Hz), 2.7-2.85 (1H, m), 3.49 (1H, d,
J=16.6 Hz), 3.59 (1H, d, J=16.6 Hz), 3.98 (2H, t, J=6.1 Hz),
4.0-4.2 (2H, m), 4.22 (1H, dd, J=10.9 Hz, 5.7 Hz), 5.0-5.1 (1H, m),
5.3-5.45 (3H, m), 6.24 (1H, s), 6.59 (1H, dd, J=8.2 Hz, 2.7 Hz),
6.69 (1H, d, J=2.7 Hz), 6.75 (1H, d, J=8.2 Hz)
Reference Example 70
4-{[4-{3-[1-Carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-(tetrahydro-4H-py-
ran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.--
D-glucopyranosyloxy)-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 48 using
4-{[4-{3-[1-benzyloxycarbonyl-1-(methyl)-ethylcarbamoyl]propoxy}-2-(tetra-
hydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pival-
oyl-.beta.-D-glucopyranosyloxy)-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-benzylo-
xycarbonyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isop-
ropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.0-1.2 (42H, m), 1.54 (6H,
s), 1.7-1.9 (2H, m), 1.95-2.15 (4H, m), 2.35-2.45 (2H, m), 2.8-2.95
(1H, m), 3.45-3.65 (4H, m), 3.8-3.9 (1H, m), 3.9-4.05 (4H, m),
4.05-4.25 (2H, m), 4.4-4.55 (1H, m), 5.15-5.3 (2H, m), 5.36 (1H, t,
J=9.4 Hz), 5.56 (1H, d, J=8.4 Hz), 6.17 (1H, brs), 6.32 (1H, d,
J=8.1 Hz), 6.41 (1H, s), 6.82 (1H, d, J=8.1 Hz)
Example 112
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(3-{1-[(piperazin-1-yl)-
carbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-methylphenyl]methyl}-1H-pyr-
azole
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1-
H-pyrazole and 1-(benzyloxycarbonyl)piperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-benzylpiperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.95-2.05 (2H, m), 2.29 (3H, s), 2.39 (2H, t, J=7.4 Hz),
2.55-2.9 (5H, m), 3.45-3.8 (11H, m), 3.85 (1H, d, J=3.2 Hz), 3.95
(2H, t, J=6.1 Hz), 5.04 (1H, d, J=7.5 Hz), 6.61 (1H, dd, J=8.2 Hz,
2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.84 (1H, d, J=8.2 Hz)
Example 113
3-(.beta.-D-Galactopyranosyloxy)-5-isopropyl-4-[(4-{3-[1-{[4-(2-hydroxyeth-
yl)-piperazin-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylph-
enyl)methyl]-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 78 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-{3-[1-carbo-
xy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1-
H-pyrazole and 1-(2-hydroxyethyl)-piperazine instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-{[4-(2-carboxyeth-
oxy)-2-methylphenyl]methyl)-5-isopropyl-1H-pyrazole and
2-amino-2-methylpropionamide, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.15 (6H, m), 1.42 (6H,
s), 1.95-2.05 (2H, m), 2.28 (3H, s), 2.3-2.55 (8H, m), 2.7-2.85
(1H, m), 3.45-3.8 (13H, m), 3.85 (1H, d, J=2.9 Hz), 3.94 (2H, t,
J=6.0 Hz), 5.04 (1H, d, J=7.6 Hz), 6.6 (1H, d, J=8.5 Hz), 6.7 (1H,
s), 6.85 (1H, d, J=8.5 Hz)
Example 114
3-(.beta.-D-Glucopyranosyloxy)-5-isopropyl-4-([4-(3-{1-[(piperazin-1-yl)ca-
rbonyl]-1-(methyl)-ethylcarbamoyl}propoxy)-2-(tetrahydro-4H-pyran-4-yloxy)-
phenyl]methyl}-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Example 105 using
4-{[4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-(tetrahydro-4H-p-
yran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-
-D-glucopyranosyloxy)-1H-pyrazole instead of
4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)met-
hyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-.beta.-D-glucopyranosyloxy)-1-
H-pyrazole.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.05-1.2 (6H, m), 1.42 (6H,
s), 1.7-1.85 (2H, m), 1.95-2.1 (4H, m), 2.38 (2H, t, J=7.4 Hz),
2.6-2.8 (4H, m), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.5-3.75 (9H,
m), 3.83 (1H, d, J=12.1 Hz), 3.9-4.0 (4H, m), 4.5-4.65 (1H, m),
5.07 (1H, d, J=7.1 Hz), 6.4 (1H, dd, J=8.3 Hz, 2.5 Hz), 6.54 (1H,
d, J=2.5 Hz), 6.89 (1H, d, J=8.3 Hz)
Reference Example 71
4-[(4-Bromo-2-fluorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-on-
e
The title compound was prepared in a similar manner to that
described in Reference Example 2 using 4-bromo-2-fluorobenzyl
bromide instead of 4-bromobenzyl bromide.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.17 (6H, d, J=7.1 Hz),
2.85-3.05 (1H, m), 3.67 (2H, s), 7.0-7.3 (3H, m)
Reference Example 72
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-bromo-2-fluo-
rophenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
4-[(4-bromo-2-fluorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-o-
ne and acetobromo-.alpha.-D-galactose instead of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one and acetobromo-.alpha.-D-glucose,
respectively.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.15-1.25 (6H, m), 1.92 (3H,
s), 1.99 (3H, s), 2.02 (3H, s), 2.18 (3H, s), 2.9-3.0 (1H, m), 3.59
(1H, d, J=16.1 Hz), 3.67 (1H, d, J=16.1 Hz), 4.05-4.25 (3H, m), 5.1
(1H, dd, J=10.4 Hz, 3.4 Hz), 5.35-5.45 (2H, m), 5.58 (1H, d, J=8.1
Hz), 6.95-7.05 (1H, m), 7.1-7.2 (2H, m)
Reference Example 73
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-carb-
oxyprop-1-enyl]-2-fluorophenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 4 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-[(4-bromo-2-flu-
orophenyl)methyl]-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromophenyl)m-
ethyl]-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.89 (3H,
s), 1.99 (3H, s), 2.01 (3H, s), 2.17 (3H, s), 2.85-3.0 (1H, m),
3.27 (2H, d, J=6.9 Hz), 3.59 (1H, d, J=16.2 Hz), 3.7 (1H, d, J=16.2
Hz), 4.05-4.3 (3H, m), 5.1 (1H, dd, J=10.2 Hz, 3.5 Hz), 5.3-5.5
(3H, m), 6.2-6.35 (1H, m), 6.43 (1H, d, J=16.2 Hz), 6.9-7.15 (3H,
m)
Reference Example 74
1-(2-Amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazine
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionic
acid (10 g) in tetrahydrofuran (20 mL) were added
1-(benzyloxycarbonyl)piperazine (16.3 g), 1-hydroxybenzotriazole
(8.02 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (11.4 g), and the mixture was stirred at room
temperature overnight. The reaction mixture was poured into water,
and the resulting mixture was extracted with ethyl acetate. The
extract was washed with water and brine, and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure. The
residue was dissolved in a mixed solvent of n-hexane and ethyl
acetate (1/1) (40 mL) at 60.degree. C. with heating, and the
solution was stirred at room temperature overnight. To the mixture
was added the same solvent (30 mL), and the mixture was further
stirred overnight. The precipitated crystals were collected by
filtration, and washed with the same solvent and dried under
reduced pressure to give
4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]pip-
erazine (13.5 g). To a solution of the obtained
4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]pip-
erazine (5 g) in tetrahydrofuran (30 mL) was added hydrochloric
acid (4 mol/L 1,4-dioxane solution, 40 mL), and the mixture was
stirred at room temperature overnight. The precipitated crystals
were collected by filtration. The obtained crystals were dissolved
in ethyl acetate and a saturated aqueous sodium hydrogen carbonate
solution. The organic layer was separated, and the organic layer
was washed with brine and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure to give the title
compound (3.65 g).
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.41 (6H, s), 3.45-3.55 (4H,
m), 3.7-3.95 (4H, br), 5.15 (2H, s), 7.25-7.4 (5H, m)
Example 115
4-{[2-Fluoro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}-
propyl)phenyl]methyl}-3-(.beta.-D-galactopyranosyloxy)-5-isopropyl-1H-pyra-
zole
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-galactopyranosyloxy)-4-({4-[(1E)-3-car-
boxyprop-1-enyl]-2-fluorophenyl}methyl)-5-isopropyl-1H-pyrazole and
1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazine
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-benzylpiperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.42 (6H,
s), 1.8-1.95 (2H, m), 2.17 (2H, t, J=7.6 Hz), 2.6 (2H, t, J=7.6
Hz), 2.7-2.85 (4H, m), 2.85-3.0 (1H, m), 3.45-3.85 (11H, m),
3.85-3.9 (1H, m), 5.09 (1H, d, J=7.8 Hz), 6.8-6.9 (2H, m), 7.0-7.15
(1H, m)
Reference Example 75
4-Bromo-2-chlorobenzyl alcohol
The title compound was prepared in a similar manner to that
described in Reference Example 14 using 4-bromo-2-chlorobenzoic
acid instead of 4-bromo-2-methylbenzoic acid.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.9-2.0 (1H, m), 4.73 (2H, d,
J=5.5 Hz), 7.3-7.45 (2H, m), 7.45-7.55 (1H, m)
Reference Example 76
4-[(4-Bromo-2-chlorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-on-
e
The title compound was prepared in a similar manner to that
described in Reference Example 15 using 4-bromo-2-chlorobenzyl
alcohol instead of 4-bromo-2-methylbenzyl alcohol.
.sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.07 (6H, d, J=6.9 Hz),
2.7-2.85 (1H, m), 3.61 (2H, s), 6.97 (1H, d, J=8.5 Hz), 7.46 (1H,
dd, J=8.5 Hz, 2.0 Hz), 7.66 (1H, d, J=2.0 Hz)
Reference Example 77
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromo-2-chloro-
phenyl)methyl]-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 12 using
4-[(4-bromo-2-chlorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-o-
ne instead of
4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-i-
sopropyl-3H-pyrazol-3-one.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.17 (6H, d, J=7.0 Hz), 1.9
(3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.07 (3H, s), 2.85-3.0 (1H,
m), 3.65 (1H, d, J=16.7 Hz), 3.74 (1H, d, J=16.7 Hz), 3.8-3.9 (1H,
m), 4.05-4.2 (1H, m), 4.31 (1H, dd, J=12.8 Hz, 4.3 Hz), 5.1-5.35
(3H, m), 5.6 (1H, d, J=8.1 Hz), 6.93 (1H, d, J=8.2 Hz), 7.24 (1H,
dd, J=8.2 Hz, 1.8 Hz), 7.49 (1H, d, J=1.8 Hz)
Reference Example 78
3-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbox-
yprop-1-enyl]-2-chlorophenyl}methyl)-5-isopropyl-1H-pyrazole
The title compound was prepared in a similar manner to that
described in Reference Example 4 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromo-2-chlor-
ophenyl)methyl]-5-isopropyl-1H-pyrazole instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-bromophenyl)m-
ethyl]-5-isopropyl-1H-pyrazole.
.sup.1H-NMR (CDCl.sub.3) .delta. ppm: 1.1-1.2 (6H, m), 1.85 (3H,
s), 2.0 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.85-3.0 (1H, m), 3.27
(2H, d, J=6.4 Hz), 3.68 (1H, d, J=16.7 Hz), 3.78 (1H, d, J=16.7
Hz), 3.8-3.9 (1H, m), 4.1-4.2 (1H, m), 4.32 (1H, dd, J=12.6 Hz, 3.8
Hz), 5.15-5.3 (3H, m), 5.43 (1H, d, J=7.8 Hz), 6.2-6.35 (1H, m),
6.42 (1H, d, J=16.1 Hz), 6.96 (1H, d, J=1.6 Hz), 7.13 (1H, dd,
J=8.2 Hz, 1.6 Hz), 7.36 (1H, d, J=1.6 Hz)
Example 116
4-{[2-Chloro-4-(3-{1-[(piperazin-1-yl)carbonyl]-1-(methyl)-ethylcarbamoyl}-
propyl)phenyl]methyl}-3-(.beta.-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazo-
le
The title compound was prepared in a similar manner to that
described in Example 99 using
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-({4-[(1E)-3-carbo-
xyprop-1-enyl]-2-chlorophenyl}methyl)-5-isopropyl-1H-pyrazole and
1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazine
instead of
3-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-
-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-p-
yrazole and 1-benzylpiperazine, respectively.
.sup.1H-NMR (CD.sub.3OD) .delta. ppm: 1.1-1.2 (6H, m), 1.43 (6H,
s), 1.8-1.95 (2H, m), 2.17 (2H, t, J=7.7 Hz), 2.59 (2H, t, J=7.6
Hz), 2.65-2.95 (5H, m), 3.25-3.45 (4H, m), 3.5-3.9 (8H, m), 5.09
(1H, d, J=7.1 Hz), 6.95-7.1 (2H, m), 7.2 (1H, d, J=1.3 Hz)
Test Example 1
Assay for Inhibitory Effects on Human SGLT1 Activity
1) Cloning and Construction of the Vector Expressing Human
SGLT1
The cDNA library was prepared for PCR amplification by reverse
transcription from total RNA deprived from human small intestine
(Ori gene) using oligo-dT as a primer. Using this cDNA library as a
template, the DNA fragment coding 1 to 2005 bp of human SGLT1
(ACCESSION: M24847), which was reported by Hediger et al., was
amplified by PCR method and inserted into the multi-cloning site of
pcDNA3.1(-) (Invitrogen). The DNA sequence inserted was perfectly
matched to the previously reported sequence.
2) Establishment of Cell Line Stably Expressing Human SGLT1
The expression vector of human SGLT1 was digested by Sca I into a
linear DNA. The linear DNA was transfected into CHO-K1 cells by
means of lipofection (Effectene Transfection Reagent: QIAGEN).
Neomycin resistant cell lines were selected by culture in the
medium containing G418 (1 mg/mL, LIFE TECHNOLOGIES), and then the
activity against the uptake of methyl-.alpha.-D-glucopyranoside was
measured by the method described below. The cell line, which showed
the greatest uptake activity, was selected and designated as
CS1-5-11D. CS1-5-11D cells were cultured in the presence of G418 at
200 .mu.g/mL.
3) Measurement of the Inhibitory Activity Against the Uptake of
methyl-.alpha.-D-glucopyranoside (.alpha.-MG)
CS1-5-11D cells were seeded into a 96-well culture plate at a
density of 3.times.10.sup.4 cells/well and cultured for 2 days, and
were used in the uptake assay. A mixture of non-labeled (Sigma) and
.sup.14C-labeled .alpha.-MG (Amersham Pharmcia Biotec) was added to
the uptake buffer (pH 7.4; containing 140 mM sodium chloride, 2 mM
potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride,
10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acid, and
5 mM tris(hydroxymethyl)aminomethane) at the final concentration of
1 mM. A test compound was dissolved in dimethyl sulfoxide, and then
appropriately diluted with distilled water. The test compound
solution was added to the uptake buffer containing 1 mM .alpha.-MG,
and designated as a measurement buffer. For the control group, the
measurement buffer without any test compound was prepared. For
measuring the basal uptake, a basal uptake measurement buffer which
contains 140 mM chorine chloride instead of sodium chloride was
prepared. After removing the culture medium of CS1-5-11D cells, 180
.mu.L of the pre-treatment buffer (the basal uptake buffer without
.alpha.-MG) was added to each well and incubated at 37.degree. C.
for 10 minutes. After repeating the same treatment, the
pre-treatment buffer was removed. To each well was added 75 .mu.L
of the measurement buffer or the basal uptake buffer was added and
incubated at 37.degree. C. for 1 hour. After removing the
measurement buffer, cells were washed twice with 180 .mu.L per well
of the washing buffer (the basal uptake buffer containing 10 mM
non-labeled .alpha.-MG). The cells were solubilized by 75 .mu.L per
well of 0.2 mol/L sodium hydroxide. The cell lysates were
transferred into PicoPlates (Packard), and then added 150 .mu.L of
MicroScint-40 (Packard) and mixed. Radioactivity was measured by
means of micro-scintillation counter TopCount (Packard). One
hundred % was set to the difference between the uptake in the
control group and the basal uptake, and the uptake of methyl
.alpha.-D-glucopyranoside at each drug concentration were
calculated. The drug concentration, at which 50% uptake of methyl
.alpha.-D-glucopyranoside was inhibited (IC.sub.50 value), was
calculated using logit plot. The results are shown in Table 1.
TABLE-US-00001 TABLE 1 Test compound IC.sub.50 value (nM) Example
15 113 Example 18 181 Example 21 12 Example 24 24 Example 27 237
Example 28 267 Example 29 431 Example 30 52 Example 31 96 Example
32 220 Example 33 174 Example 34 245 Example 35 115 Example 48 31
Example 57 39 Example 61 18
Test Example 2
Assay for Inhibitory Effects on Blood Glucose Level Increase in
Rats
1) Preparation of Diabetic Rat Model
Male wistar rats (Japan Charles River), aged 8 weeks old, were
injected nicotinamide (230 mg/kg) intraperitoneally. Fifteen
minutes after injection, they were injected streptozotocin (85
mg/kg) intravenously from tail vain under anesthesia with ether.
After a week, rats were fasted overnight and then glucose tolerance
test (2 g/kg) was done. The rats which showed plasma glucose
concentration at 1 hour after glucose loadwas over 300 mg/dL were
selected to use liquidmeal tolerance test.
2) Liquid Meal Tolerance Test
After overnight fasted, the diabetic rats were orally administered
a test compound (1 mg/kg), which was dissolved in distilled water,
in the drug-treating group, or distilled water alone in a control
group. Immediately after the compound administration, 17.25 kcal/kg
of liquid meal (No. 038, Control diet, assorted with dextrin and
maltose; Oriental Yeast Co., Ltd.) was loaded orally. The blood was
collected from tail artery immediately before and after
administration with the time course, and treated with heparin
immediately. The blood was centrifuged, and the plasma was
collected to quantify the plasma glucose concentration by glucose
oxidase method. Plasma glucose concentrations at pretreatment (0
h), 0.5 and 1 hour after the drug administration are shown in Table
2. The values in the table are presented as the mean.+-.S.E.
TABLE-US-00002 TABLE 2 Test Plasma glucose concentration (mg/dL)
compound 0 h 0.5 h 1 h Control 117 .+-. 8 326 .+-. 46 297 .+-. 35
Example 21 118 .+-. 9 156 .+-. 15 178 .+-. 19 Control 121 .+-. 7
313 .+-. 33 303 .+-. 63 Example 30 121 .+-. 6 163 .+-. 8 187 .+-. 9
Control 140 .+-. 11 280 .+-. 22 287 .+-. 23 Example 32 125 .+-. 8
223 .+-. 20 278 .+-. 32 Example 33 127 .+-. 11 207 .+-. 8 251 .+-.
21 Control 116 .+-. 11 241 .+-. 15 237 .+-. 10 Example 48 112 .+-.
5 139 .+-. 4 132 .+-. 4 Control 133 .+-. 9 236 .+-. 9 210 .+-. 11
Example 57 126 .+-. 6 149 .+-. 7 158 .+-. 10 Control 122 .+-. 6 277
.+-. 16 272 .+-. 21 Example 61 116 .+-. 6 136 .+-. 6 172 .+-.
37
Test Example 3
Acute Toxicity Test
Male ICR mice (CLEA Japan, Inc.; 32-37 g, n=5), aged 6 weeks old,
were fasted for 4 hours. A test compound, which was dissolved in
distilled water, was administered orally at a dose of 1 g/kg, and
then mice were observed for 24 hours. The results are shown in the
following Table 3.
TABLE-US-00003 TABLE 3 Test compound Number of death Example 57
0/5
INDUSTRIAL APPLICABILITY
The pyrazole derivatives represented by the above general formula
(I) of the present invention, pharmaceutically acceptable salts
thereof and prodrugs thereof exert an inhibitory activity inhuman
SGLT1 and can suppress increase of blood glucose level by
inhibiting absorption of carbohydrate such as glucose at the small
intestine, and particularly, can normalize postprandial
hyperglycemia by delaying carbohydrate absorption based on the
mechanism. Therefore, the present invention can provide excellent
agents for the prevention or treatment of a disease associated with
hyperglycemia such as diabetes, impaired glucose tolerance,
diabetic complications, obesity or the like. In addition, since the
pyrazole derivatives represented by the above general formula (II)
of the present invention and salts thereof are important as
intermediates in the production of the pyrazole derivatives
represented by the above general formula (I), the compounds
represented by the above general formula (I) of the present
invention can be readily prepared via such compounds.
* * * * *